neuromeres have been identified. The prosencephalon gives rise to the
Mesencephalon (or Cerebral peduncles
telencephalon, diencephalon 1 (D1) and diencephalon 2 (D2), which
midbrain) Tegmentum
has three subdivisions. The mesencephalon is subdivided into mesen- Tectum
cephalon 1 (M1) and mesencephalon 2 (M2). The rhombencephalon Aqueduct
is subdivided into the isthmus rhombencephali and rhombomeres 1–8;
Prosencephalon (or forebrain)
the original rhombomere A gives rise to secondary rhombomeres 1, 2
1. Diencephalon Thalamus
and 3; rhombomere B gives rise to secondary rhombomere 4; rhom- Metathalamus
bomere C gives rise to secondary rhombomeres 5, 6 and 7; and rhom- Subthalamus
bomere D gives rise to secondary rhombomere 8 (O’Rahilly and Müller Epithalamus
1999). As the rhombencephalon grows, the rhombomeric boundaries Caudal part of the hypothalamus
Caudal part of the third ventricle
become less distinct. With the early appearance of the cerebellum from
2. Telencephalon Rostral part of the hypothalamus
the isthmus rhombencephali and rhombomere 1, the rhomben-
Rostral part of the third ventricle
cephalon is traditionally divided into the metencephalon, which Cerebral hemispheres
extends to about rhombomere 3, and the myelencephalon, which Lateral ventricles
extends to the spinomedullary junction. A summary of the derivatives Cortex (archaeocortex, palaeocortex, neocortex)
of the cerebral regions is given in Table 17.1. Corpus striatum
The elongation of the brain occurs at the same time as the appear-
ance of three flexures, which also appear prior to the closure of the
neural tube; two are concave ventrally and one concave dorsally. During


stages 13 and 14, the brain bends at the mesencephalon (mesencephalic
flexure) so that the prosencephalon bends in a ventral direction around


DEvEloPmENT of THE NERvous sysTEm
240
3
NoITCEs
A B
Oculomotor nerve
Isthmus rhombencephali
Trochlear nerve
Pontine flexure Margin of optic cup Isthmus
Choroid fissure
Mesencephalic flexure
Otocyst Cerebellum Optic rudiment
Cervical flexure Motor root
Trigeminal nerve
Sensory root
Facial and
vestibulocochlear nerves Abducens nerve
Spinal cord
Glossopharyngeal nerve
Vagus nerve
Hypoglossal nerve
C Accessory nerve
Oculomotor nerve
Mammillary
body 3 brain regions 5 brain regions
Rudiment of
Telencephalon
olfactory bulb Prosencephalon
Optic stalk
Diencephalon
Hypophysis
Rhombic lip Trigeminal nerve Mesencephalon Mesencephalon
Pontine flexure Facial and vestibulocochlear nerves Metencephalon
Rhombencephalon
Glossopharyngeal nerve
Myelencephalon
Vagus nerve
Hypoglossal nerve
Spinal cord
Accessory nerve
and lower rootlets
Fig. 17.3 Formation of the mesencephalic, cervical and pontine flexures; human embryos, lateral views. The roof of the rhombencephalon has been
removed in each case. A, 9 mm long. B, approximately 10.2 mm long. C, 13.6 mm long.
the cephalic end of the notochord and foregut until its floor lies almost modulates signalling pathways for Shh, Wnt and PDGFα (Lee and
parallel with that of the rhombencephalon (Fig. 17.3). A bend also Gleeson 2010).
appears at the junction of the rhombencephalon and spinal cord (cervi- The neuroepithelium contains stem cells that will give rise to popu-
cal flexure). This increases from the fifth week to the end of the seventh, lations of neuroblasts and glioblasts. A population of radial glia, each
by which time the rhombencephalon forms nearly a right angle to the with a primary cilium, differentiates very early. They elongate as the


spinal cord. However, after the seventh week, extension of the head epithelium develops, maintaining contact with both the lumen and the
takes place and the cervical flexure diminishes and eventually disap- outer surface, and provide a scaffold on which cell progeny can migrate.
pears. The third bend, the pontine flexure, is directed ventrally between Arl13b, a cilia-specific small guanosine triphosphatase (GTPase), is
the metencephalon and myelencephalon. It does not substantially essential for the formation of radial glia (Higginbotham et al 2013).
affect the outline of the head. In this region, the roof plate thins until Three zones or layers develop, termed ventricular, mantle and mar-
it is composed only of a single layer of cells and pia mater: the tela ginal zones (Figs 17.4–17.6). The inner, ventricular zone (germinal,
choroidea. The flexure of the neural tube at this point produces a primitive ependymal or matrix layer) corresponds to the apical region
rhombic shape in the roof, which later forms the medullary velum. of the radial glial cells and contains the nucleated parts of the columnar
cells and rounded cells undergoing mitosis. The mantle, or intermedi-
ate, zone contains the migrant cells from the divisions occurring in the
EARLY CELLULAR ARRANGEMENT OF
ventricular zone. The outer, marginal zone initially consists of the exter-
THE NEURAL TUBE nal (basal) cytoplasmic processes of the radial glia. It is soon invaded
by tracts of axonal processes that grow from neuroblasts developing in
The dorsoventral patterning of the neural tube is initiated by the under- the mantle zone, together with varieties of non-neuronal cells (glial
lying notochord. As neurulation proceeds, the neural tube elongates by cells and, later, vascular endothelium and perivascular mesenchyme).
convergent extension (Bay and Caspary 2012). Histologically, the early For further development of these layers, see page 245.
neural tube is composed of a pseudostratified neuroepithelium, in At first, the neural tube caudal to the brain is oval in transverse


which the apical surfaces of the cells face the lumen of the neural tube section and its lumen is narrow and slit-like (see Fig. 17.4). The original
and their basal surfaces contact the outer limiting layer of neural crest floor plate and the dorsal site of fusion of the tube initially contain
mesenchyme, which will become the pia mater. Initially, each cell has non-neural cells. With cellular proliferation, the lateral walls thicken
an apical, non-motile primary cilium with an internal 9 + 0 configura- and the lumen, now the central canal, widens in its dorsal part and is
tion of microtubules and a system of intraflagellar transport. The mem- somewhat diamond-shaped on cross-section (see Fig. 17.6). The widen-
brane of the primary cilium expresses receptors and ion channels, and ing of the canal is associated with the development of a longitudinal


Neural crest
241
71
RETPAHC
sulcus limitans on each side, dividing the ventricular and mantle (inter- structure or function of the primary cilium are associated with changes
mediate) zones in each lateral wall into a ventrolateral lamina or basal in cortical formation that are thought to underlie cognitive deficits and
plate, and a dorsolateral lamina or alar plate, respectively. This separa- mental retardation in a range of recessive ciliopathies (Higginbotham
tion underlies a fundamental functional difference. et al 2013).
Throughout the neural tube, a generic pattern in the position of the
neurones is specified by the juxtaposition of the notochord to the
NEURAL CREST
neural tube. Experimental lateral or dorsal grafting of a notochord
results in the induction of a floor plate overlying the grafted notochord
and the induction of ectopic motor neurones dorsally. Similarly, lateral The neuronal populations of the early epiblast become arranged in the
or dorsal grafts of a floor plate also result in the induction of a new medial region of the embryonic disc as the neural plate. Laterally, neural
floor plate overlying the graft and the induction of ectopic dorsal motor folds or crests indicate the transitional region between neural and
neurones. Removal of the notochord results in the elimination of surface ectoderm. Along most of the neuraxis, the cells at the tips of the
the floor plate and the motor neurones, and the differentiation of neural folds undergo an epithelial/mesenchyme transformation. They
dorsal cell types in the ventral region of the cord (Dodd et al 1998) acquire migratory properties and leave the epithelium just prior to its
(Fig. 17.7). fusion with the contralateral fold in the dorsal midline. The migratory
The basal plate is normally concerned predominantly with motor cells so formed are collectively termed the neural crest. Cells within the
function, and contains the cell bodies of motor neurones that will rostral prosencephalic neural fold and smaller populations of cells in
occupy the future anterior and lateral grey columns. The alar plate bilateral sites lateral to the early brain do not form migratory neural


receives sensory inflow from external dorsal root ganglia. Motor and crest cells but remain within the surface epithelium as ectodermal
sensory axons combine to form the mixed nerves. placodes.
Neural crest populations arise from the neural folds as primary
neurulation proceeds and simultaneously progresses rostrally and cau-
FAILURE OF NEURULATION dally. Crest cells migrate from the neural folds of the brain prior to
tube closure. Caudally, from approximately somite 29, secondary neu-
Failure of neurulation produces the conditions of craniorachischisis rulation processes produce the most caudal neural crest. Two distinct
totalis (where the entire neural tube is unfused in the dorsal midline), populations of neural crest cells are formed: a neuronal population
cranioschisis or anencephaly (where the neural tube is fused dorsally produced throughout the brain and spinal cord, which gives rise to
to form the spinal cord but is not fused dorsally in the brain), and spina sensory and autonomic neurones and glia; and a non-neuronal mesen-
bifida (where local regions of the spinal neural tube are unfused, or chymal population, which arises only from the brain (Figs 17.9–
there is failure of formation of the vertebral neural arches) (Fig. 17.8; 17.10). Melanocytes develop from a subpopulation of neural crest cells
see also Ch. 44). Anencephalic fetuses display severe disturbances in derived from both the head and the trunk. They form one of the three
the shape, position and ossification of the basichondrocranium and in pigment cell types (the others being retinal pigment epithelium and
the course of the intracranial notochord, and so the condition is more the pigment cells of the pineal organ, which both originate from the
complicated than ‘simply’ a failure of neural tube fusion. Defects in the diencephalon).
Primitive ependymal layer
Roof plate (matrix cell layer) Oval bundle
Roof plate (ventricular zone) Dorsal spinal
nerve root
Oval bundle
Fibres of ventral Spinal (dorsal root) ganglion
spinal nerve root
Dorsal spinal nerve rootlet Cells of mantle
layer (intermediate
zone) forming anterior
Central canal horn of grey matter


Ventricular zone
Intermediate (mantle) zone
Ventral spinal nerve rootlet
Marginal zone
Spinal nerve Floor plate Notochord Marginal layer (zone)
Floor plate trunk
Fig. 17.4 The spinal cord of a 4-week-old human embryo. Transverse Fig. 17.6 The spinal cord in the cervical region of a human embryo early
section. in the sixth week; crown–rump length 8 mm. Transverse section.
Pial surface
Marginal zone
Radial glial cells
Pial surface
Intermediate
(mantle) zone
Marginal zone
Pial surface
Ventricular zone/
Ventricular zone
germinal matrix
Ventricular surface Ventricular surface Ventricular surface
Fig. 17.5 The early development of the neural tube. Three layers are delineated in the spinal cord and brainstem.


DEvEloPmENT of THE NERvous sysTEm
242
3
NoITCEs
A Neural plate B Neural fold C Neural tube D Spinal cord E F G H
Dorsal neurones (Alar plate) Roof plate Notochord
Motor neurones (Basal plate) Floor plate
Fig. 17.7 A–D, Successive stages in the development of the neural tube and spinal cord. A, The neural plate consists of epithelial cells. Cells in the
midline of the neural plate are contacted directly by the notochord. More lateral regions of the neural plate overlie the paraxial mesenchyme (not shown).
B, During neurulation, the neural plate bends at its midline and this elevates the lateral edges of the plate as the neural folds. Contact between the
midline of the neural plate and the notochord is maintained at this stage. C, The neural tube is formed when the dorsal tips of the neural folds fuse. Cells
in the region of fusion form the roof plate, a specialized group of dorsal midline cells. D, Cells at the ventral midline of the neural tube retain proximity to
the notochord and differentiate into the floor plate. After neural tube closure, neuroepithelial cells continue to proliferate and eventually differentiate into
defined classes of neurones at different dorsoventral positions within the spinal cord. For example, sensory relay, commissural and other classes of
dorsal neurones differentiate near to the roof plate, and motor neurones differentiate ventrally near the floor plate, which, by this time, is no longer in
contact with the notochord. E–H, A summary of the results obtained from experiments in chick embryos, in which either a notochord or floor plate is
grafted to the dorsal midline of the neural tube, or the notochord is removed before neural tube closure. E, The normal condition: motor neurones are
located ventrally and sensory relay neurones are located dorsally. F, Dorsal grafts of a notochord result in the induction of a floor plate in the dorsal
midline and ectopic dorsal motor neurones. G, Dorsal grafts of a floor plate induce a new floor plate in the dorsal midline and ectopic dorsal motor


neurones. H, Removal of the notochord results in the elimination of the floor plate and motor neurones, and the expression of dorsal cell types in the
ventral region of the spinal cord.
A B
Entire neural tube
remains open
Herniated Herniated
brain arachnoid
tissue mater
Craniorachischisis Anencephaly Meningoencephalocoele Meningoencephalocoele
C Open spinal cord Dura and arachnoid mater Spinal cord Dura and arachnoid mater Subarachnoid space
containing CSF
Channel open Subarachnoid Spinal cord
due to incomplete space containing
vertebral arch CSF
Myelocoele Meningomyelocoele Meningocoele
Fig. 17.8 Defects caused by failure of neural tube formation. A, Total failure of neurulation. B, Failure of rostral neurulation. C, Failure of caudal
neurulation. Abbreviations: CSF, cerebrospinal fluid.
In the trunk, the migration patterns of neural crest cells are chan- (Müller and O’Rahilly 1997). Eight main rhombomeres extend from
nelled by the somites. As the crest cells move laterally and ventrally, the midbrain–hindbrain boundary rostrally to the spinal cord caudally
they can pass between the somites and within the rostral sclerotomal (see Fig. 17.2). Rhombomeres 8 and 7 give rise to neural crest cells that
half of each somite, but they cannot penetrate the caudal moiety of the migrate into the fourth and sixth pharyngeal arches; rhombomere 6
sclerotomal mesenchyme. Thus, the segmental distribution of the spinal crest cells invade pharyngeal arch 3. Rhombomere 4 crest cells migrate
and sympathetic ganglia is imposed on the neural crest cells by a pre- into arch 2, whereas rhombomeres 5 and 3 give rise to a very small
pattern that exists within the somitic paraxial mesenchyme (Fig. 17.11). number of neural crest cells that migrate rostrally and caudally to enter


The origin of the cranial–caudal patterning of the ventral neural crest the adjacent even-numbered neighbours. Rhombomeres 1 and 2 pro-
cells is not clear. duce crest cells that invade the first pharyngeal arch. In each rhom-
Rostral to the otic vesicle, neural crest cells arise from specific regions bomere, mesenchymal populations and the sensory and autonomic
of the brain. Early in development, a number of transverse subdivisions ganglia are formed from the crest cells (see Fig. 12.4).
perpendicular to the long axis of the brain can be seen within the Further rostrally, neural crest from the mesencephalon migrates
rhombencephalon, dividing it into segments termed rhombomeres into the first arch maxillary and mandibular processes. Crest cells are


Ectodermal placodes
243
71
RETPAHC
Developmental
A Fate map B potentials
PROSENCEPHALON
MESENCEPHALON
ROSTRAL
RHOMBENCEPHALON
S1
CAUDAL
S5
S7
CERVICAL
SPINAL CORD
S18
THORACIC
S24 SPINAL CORD
S28
LUMBOSACRALL
SPINAL CORD
Mesectoderm Sensory ganglion
Ectomesenchyme Sympathetic ganglia
Parasympathetic
ganglia Fig. 17.10 A fate map of the rostral region of the neural primordium, as
established by the quail–chick chimera system. A, The various territories
Fig. 17.9 A, A fate map along the neural crest of the presumptive
yielding rostral head are indicated on the neural plate and neural fold of a
territories that yield ectomesenchyme, sensory, parasympathetic and
1–3-somite embryo. B, The results obtained in the avian embryo have
sympathetic ganglia, and neural crest-derived mesenchyme in normal
been extrapolated to the human head. For example, the neural fold area
development. B, Developmental potentials for the same cell types. If
coloured green in A yields the epithelium of the nose, philtrum and
neural crest cells from any level of the neural axis are implanted into the
primary palate.
appropriate sites of a host embryo, they can give rise to almost all the
cell types forming the various kinds of peripheral nervous system ganglia.
This is not true for neural crest-derived mesenchyme, whose precursors
are confined to the cephalic area of the crest down to the level of somite
5. Abbreviations: S, somite.
produced from the diencephalon up to the level of the pineal gland
(epiphysis). Neural crest cells that are produced from this rostral portion
of the brain contribute mesenchymal populations to the frontonasal
process. The most rostral prosencephalic neural fold does not give rise
to neural crest.
ECTODERMAL PLACODES
Before the neural tube closes, the elevating neural folds contain two
distinctive neuronal populations. The larger population, neural crest


cells, migrates from the neural epithelium prior to neural tube fusion.
The smaller population, neuroepithelial cells, becomes incorporated
into the surface ectoderm after neural tube closure. These areas of
neuroepithelium within the surface ectoderm have been termed ecto-
dermal placodes. Although the majority of the ectodermal placodes
form nervous tissue, non-neurogenic placodes also occur (Begbie and
Graham 2001). After an appropriate inductive stimulus, the placodes
thicken and either they generate migratory neuronal cells that will
contribute to the cranial sensory ganglia, or the whole placodal region
invaginates to form a vesicle beneath the remaining surface ectoderm.
Neurogenic placodes undergo both processes. Paired non-neurogenic
placodes invaginate to form the lens vesicles under the inductive influ-
ence of the optic vesicles (Ch. 40).
nolahpecnesorP
Frontonasal
ectoderm
nolahpecneseM
Hypothalamus Adenohypophysis
Nasal cavity
Olfactory placode
Telencephalon
Eye
Optic placode
Neurohypophysis
Pineal gland Maxillo- (epiphysis) mandibular
ectoderm
and
Thalamus
trigeminal
placode
Trigeminal placode
Mesencephalon
Nasal cavity
Philtrum
Primary palate
Maxilla
Secondary palate
Mandible
Derived from tissues
of several branchial
arches not included
in this diagram
Neural crest cells Melanocytes
Dorsal root
Ganglia and glia of ganglia and
sympathetic trunk glia
Pre-aortic Enteric Medulla of
ganglia and glia ganglia and glia suprarenal gland
Fig. 17.11 The migration routes taken by neural crest cells in the trunk.


DEvEloPmENT of THE NERvous sysTEm
244
3
NoITCEs
The neural folds meet in the rostral midline adjacent to the bucco- glosso pharyngeal (petrosal) and vagus (nodose) nerves, respectively.
pharyngeal membrane. This rostral neural fold does not generate These placodes thicken and cells begin to detach from their epithelium
neural crest but gives rise to the hypophysial placode, i.e. the future soon after the pharyngeal pouches have contacted the overlying ecto-
Rathke’s pouch, which remains within the surface ectoderm directly derm. Concurrently, the neural crest cells reach and move beyond these
rostral to the buccopharyngeal membrane. The rostral neural fold also lateral extensions of the pharynx. Neurones migrate from the epi-
gives rise to the olfactory placodes, which remain as paired, laterally branchial placodes internally to the sites of ganglion formation, where
placed placodes, and to the epithelium of the nasal cavity (see they show signs of early differentiation into neurones, including the
Fig. 17.10). formation of neurites.
Further caudally, similar neurogenic placodes can be identified and The otic placodes, located lateral to the myelencephalon, invaginate
divided into three categories: namely, the epibranchial, otic and trigem- to form otic vesicles from which the membranous labyrinth of the ear
inal placodes (Fig. 17.12). The epibranchial placodes appear in the develops. Neurones of the vestibulocochlear nerve ganglia arise from
surface ectoderm immediately dorsal to the area of pharyngeal neurones that bud off the ventromedial aspect of the otic cup, after
(branchial) cleft formation. The first epibranchial placode is located at which they can be distinguished in the acoustic and vestibular ganglia
the level of the first pharyngeal groove and contributes cells to the distal (Ch. 39).
(geniculate) ganglion of the facial nerve; and the second and third The profundal and maxillomandibular trigeminal placodes, which


epibranchial placodes contribute cells to the distal ganglia of the fuse in humans to form a single entity, lie rostral of the otic placodes,
alongside the mesencephalic–rhombencephalic junction. Prospective
neuroblasts migrate from foci dispersed throughout the surface ecto-
derm lateral and ventrolateral to the caudal mesencephalon and
metencephalon to contribute to the distal portions of the trigeminal
ganglia.
Fig. 17.12 A scheme of a human embryo at stage 13 (4 mm, 32 somites),
rendered flat to eliminate the cerebral flexures. The cranial sensory
ganglia and otocyst, derived from the epibranchial placodes, are shown
on the left. The levels of origin of the neural crest that contribute to the
cranial sensory ganglia and mesenchymal populations in the head are
indicated on the right. This arrangement may vary in other species.
(Courtesy of Professor R O’Rahilly and Dr F Müller.)
setimoS seremorueN tserc
larueN
Telencephalon
Diencephalon
1
Optic vesicle
2
Mesencephalon 1
2
Isthmus
Rhombomere 1
V 2
3
VII 4
VIII
5
IX Otocyst 6
X 7
S1
8
Cerebrospinal
junction
sedocalp
laegnyrahpipE
ailgnag
lainarC
Nasal
Fig. 17.13 A scanning
Optic electron micrograph
of the roof of the
pharynx showing the
invagination of placodal
ectoderm to form the
adenohypophysis
(Rathke’s pouch,
Mesencephalic
arrow) and choanal
membranes
(arrowheads).
(Photograph by P
Collins; printed by
S Cox, Electron
Microscopy Unit,
Southampton General
Hospital.)
Trigeminal
Facial/
vestibular
A
Otic
Hypophysial recess Mesencephalon
Glossopharyngeal (Pouch of Rathke)
Vagal
Buccopharyngeal
membrane
Notochord
2 Pericardium Foregut
Hypoglossal
3
4


B Diencephalon Mesencephalon
Spinal Interventricular foramen Neurohypophysis
Telencephalon Diencephalon Mesencephalon Rhombencephalon Telencephalon Adenohypophysis
Notochord
First arch: ventral (mandibular) part Degenerated buccopharyngeal membrane
Fig. 17.14 A–B, Sagittal sections of heads of early embryos showing
initial stages in the development of the hypophysis.


mechanisms of neural development
245
71
RETPAHC
PITUITARY GLAND (HYPOPHYSIS CEREBRI) astrocyte-like support cells in the enteric nervous system. Angioblastic
mesenchyme gives rise to a variety of blood cell types, including circu-
The hypophysis cerebri consists of the adenohypophysis and the neuro- lating monocytes that infiltrate the brain as microglial cells later in
hypophysis (Ch. 23). Prior to neurulation, the cell populations that give development (Ch. 3).
rise to these two portions of the pituitary gland are found next to each In the CNS, cells of the proliferating ventricular zone give rise to
other within the rostral portion of the floor of the neural plate and the astrocytes and oligodendrocytes. After the proliferative phase, the cells
contiguous midline neural fold. As neurulation proceeds, the future remaining at the ventricular surface differentiate into ependymal cells,
neurohypophysis remains within the floor of the prosencephalon. The which are specialized in many regions of the ventricular system as cir-
cells of the future adenohypophysis are displaced into the surface ecto- cumventricular organs. Planar cell polarity (PCP) genes are involved in
derm, where they form the hypophysial placode in close apposition and the differentiation of ependymal cells into a ciliated epithelium (Tissir
adherent to the overlying prosencephalon. and Goffinet 2010). PCP signalling regulates the position of the ciliary
The most rostral portion of the neural plate, which will form the basal bodies. Defects in basal body polarity lead to disorganized beating
hypothalamus, is in contact rostrally with the future adenohypophysis of cilia and impaired direction of flow of the cerebrospinal fluid (Wall-
in the rostral neural ridge, and caudally with the neurohypophysis, in ingford 2010), and this may result in defects in neuronal migration as
the floor of the neural plate (see Fig. 17.10). After neurulation, the cells development proceeds (Sawamoto et al 2006).


of the rostral neural ridge remain in the surface ectoderm and form the The ventricular zone lining the early central canal of the spinal cord
hypophysial placode, which is in close apposition and adherent to the and the cavities of the brain gives rise to neurones and glial cells (see
overlying prosencephalon. Figs 17.4–17.5). Radial glia are specialized glia with radial processes
Neural crest mesenchyme later moves between the prosencephalon that extend both outwards to form the outer limiting membrane deep
and surface ectoderm, except at the region of the placode. Before rupture to the pia mater, and inwards to form the inner limiting membrane
of the buccopharyngeal membrane, proliferation of the periplacodal around the central cavity. These processes may provide contact guidance
mesenchyme means that the placode forms the roof and walls of a sac- paths for cell migrations, both neuronic and glioblastic. A secondary
cular depression. This hypophysial recess (pouch of Rathke; Figs 17.13– radial glial scaffold is formed in the late developing cerebellum and
17.14) is the rudiment of the adenohypophysis. It lies immediately dentate gyrus, and serves to translocate neurones, formed in secondary
ventral to the dorsal border of the buccopharyngeal membrane, extend- germinal centres, to their definitive adult locations. Radial glia eventu-
ing in front of the rostral tip of the notochord, and retaining contact ally lose their connections with both inner and outer limiting mem-
with the ventral surface of the prosencephalon, which will become the branes, except those persisting in the retina as Müller cells, in the
hypothalamus. It is constricted by continued proliferation of the sur- cerebellum as Bergmann glia and in the hypothalamus as tanycytes.
rounding mesenchyme to form a closed vesicle, but remains, for a time, They can differentiate into neurones as well as astrocytes. They may
connected to the ectoderm of the stomodeum by a solid cord of cells, partially clothe the somata of neighbouring developing neurones


which can be traced down the posterior edge of the nasal septum. (between presumptive synaptic contacts), or similarly enwrap the inter-
Masses of epithelial cells form, mainly on each side and in the ventral synaptic surfaces of their neurites. Glial processes may expand around
wall of the vesicle, and the development of the adenohypophysis intraneural capillaries as perivascular end-feet. Other glioblasts retain
progresses by the ingrowth of a mesenchymal stroma. Differentiation an attachment (or form new expansions) to the pia mater, the inner-
of epithelial cells into stem cells and three differentiating types is said most stratum of the meninges, as pial end-feet. Glioblasts also line the
to be apparent during the early months of fetal development. It has central canal and cavities of the brain as generalized or specialized
been suggested that different types of cells arise in succession, and that ependymal cells, but lose their peripheral attachments. In some situa-
they may be derived in differing proportions from different parts of the tions, e.g. the ventral (anterior) median fissure of the spinal cord,
hypophysial recess. A craniopharyngeal canal, which sometimes runs ependymal cells retain their attachments to both the inner and the outer
from the rostral part of the hypophysial fossa of the sphenoid to the limiting membranes. Glia function as perineuronal satellites, providing
exterior of the skull, is often said to mark the original position of the cellular channels that connect extracerebral and intraventricular cere-
hypophysial recess. Traces of the stomodeal end of the recess are usually brospinal fluid, the cerebral vascular bed, the intercellular crevices of
present at the junction of the septum of the nose with the palate. Others the neuropil, and the cytoplasm of all neural cell varieties.
have claimed that the craniopharyngeal canal itself is a secondary for- Microglia appear in the CNS after it has been penetrated by blood
mation caused by the growth of blood vessels, and is quite unconnected vessels and invade it in large numbers from certain restricted regions;
with the stalk of the adenohypophysis. from here, they spread in what have picturesquely been called ‘fountains


A small endodermal diverticulum, Seessel’s pouch, projects towards of microglia’, to extend deeply among the nervous elements (Ch. 3).
the brain from the cranial end of the foregut, immediately caudal to
the buccopharyngeal membrane. In some marsupials, this pouch forms
MECHANISMS OF NEURAL DEVELOPMENT
a part of the hypophysis but, in humans, it is not well defined and
disappears entirely.
Just caudal to, but in contact with, the adenohypophysial recess, a For more than a century, the mechanisms that operate during the devel-
hollow diverticulum elongates towards the stomodeum from the floor opment of the nervous system have been studied experimentally; while
of the neural plate just caudal to the hypothalamus (see Fig. 17.14B); much has been established, answers to many fundamental questions
this region of neural outgrowth is the neurohypophysis. It forms an remain obscure. Significant advances in our understanding of the mech-
infundibular sac; its walls increase in thickness until the lumen is oblit- anisms that regulate the behaviour of early neural populations are
erated, except at its upper end, where it persists as the infundibular based on work on amphibian, chicken, mouse and fish embryos, using
recess of the third ventricle. The neurohypophysis becomes invested by a combination of genetic, embryological, biochemical and molecular
the adenohypophysis, which extends dorsally on either side. The adeno- techniques.
hypophysis gives off two processes from its ventral wall that grow along The CNS has a fundamental structure of layers and cells, which are
the infundibulum and fuse to surround it, coming into relation all derived from a pluripotential neuroepithelium. Developing neu-
with the tuber cinereum and forming the tuberal portion of the hypo- rones produce axons that traverse great distances to reach their target
physis. The original lumen of Rathke’s pouch remains first as a cleft, organs. Within the CNS, they form myriad connections with other
and later as scattered vesicles, and can be identified readily in sagittal neurones in response to locally secreted cues.
sections through the mature gland. The dorsal wall of Rathke’s pouch


remains thin and fuses with the adjoining part of the neurohypophysis
HISTOGENESIS OF THE NEURAL TUBE
as the pars intermedia.
At birth, the hypophysis is about one-sixth of the weight of the adult
gland; it increases in weight to become about one-half of the weight of The wall of the early neural tube consists of an internal ventricular zone
the adult gland at 7 years, and attains adult weight at puberty. Through- (sometimes termed the germinal matrix) abutting the central lumen. It
out postnatal life, the gland appears larger in females, in both size and contains the apical, nucleated parts of the pseudostratified columnar
weight. neuroepithelial cells and rounded cells undergoing mitosis. The early
ventricular zone also contains a population of radial glial cells, whose
processes pass from the ventricular surface to the pial surface, thus
NEUROGLIA
forming the internal and external glia limitans (glial limiting mem-
brane). As development proceeds, the early, pseudostratified epithelium
Glial cells that support neurones in the CNS and PNS are derived from proliferates and an outer layer, the marginal zone, devoid of nuclei but
three lineages: namely, neuroectoderm, neural crest and angioblastic containing the external cytoplasmic processes of cells, is delineated.
mesenchyme. In the PNS, neural crest cells produce Schwann cells and Subsequently, a middle, mantle layer (intermediate zone) forms as the


Development of the nervous system
245.e1
71
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Mouse embryonic stem cells in three-dimensional culture, induced
to form co-cultures of rostral hypothalamic neuroepithelium and oral
ectoderm, spontaneously self-sort and form oral ectodermal epithelial
pouches, of similar dimensions to Rathke’s pouch and expressing the
pituitary placode marker Lim3. Multiple pouches form under these
experimental conditions, suggesting that the process of pouch forma-
tion per se (including morphogenesis and rough size determination) is
driven locally by an intrinsic self-organizing mechanism, whereas the
specific place and number of pituitary placodes are under the control
of complex positional instructions from region-specific regulators
(Sasai et al 2012).


DEvEloPmENT of THE NERvous sysTEm
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3
NoITCEs
through the developing nervous tissue, and finish their migrations in
Intermediate zone various definitive sites where they differentiate into neurones or mac-
roglial cells. In the cerebral hemispheres, a zone termed the cortical
plate is formed outside the intermediate zone by radially migrating cells
from the ventricular zone. The most recently formed cells migrate to
the outermost layers of the cortical plate, so that earlier-formed and
DNA synthesis
Ventricular in this part of migrating cells become subjacent to those migrating at a later time. The
zone/ ventricular zone subplate zone is an additional transient stratum found deep to the early
germinal cortical plate in the forebrain.
matrix
LINEAGE AND GROWTH IN THE NERVOUS SYSTEM
Apical cell surface
Neurones are derived from three embryonic sources: CNS neurones
originate from the pluripotential neural plate and tube, whereas gan-
glionic neurones originate from the neural crest and ectodermal pla-
Ventricle codes. The neural plate also provides ependymal and macroglial cells.
Peripheral Schwann cells and chromaffin cells arise from the neural
crest. The origins and lineages of cells in the nervous system have been
Fig. 17.15 The cell cycle in the ventricular zone of the developing neural determined experimentally by the use of autoradiography, microinjec-
tube. The nuclei of the proliferating stem cells show interkinetic migration. tion or retroviral labelling of progenitor cells, in cell culture.
(Reprinted with permission from Journal of Comparative Neurology 120: During development, neurones are formed before glial cells. The
37–42, S Fujita, 1963. Wiley-Liss.) timing of events differs in various parts of the CNS and between species.
Most neurones are formed prenatally in mammals but some postnatal
neurogenesis does occur, e.g. the small granular cells of the cerebellum,
newly formed neurones migrate ventriculofugally from the ventricular olfactory bulb and hippocampus, and neurones of the cerebral cortex.
zone (see Fig. 17.5). Gliogenesis continues after birth in periventricular and other sites. Dif-


Most CNS cells are produced in the proliferative zone adjacent to ferent classes of neurones develop at specific times. Large neurones,
the future ventricular system; in some regions, this area is the only such as principal projection neurones, tend to differentiate before small
actively mitotic zone. According to the monophyletic theory of neuro- ones, such as local circuit neurones. However, their subsequent migra-
genesis, it is assumed to produce all cell types. The early neural epithe- tion appears to be independent of the times of their initial formation.
lium, including the deeply placed ventricular mitotic zone, consists of Neurones can migrate extensively through populations of maturing,
a homogeneous population of pluripotent cells whose varying appear- relatively static cells, to reach their destination, e.g. cerebellar granule
ances reflect different phases in a proliferative cycle. The ventricular cells pass through a layer of Purkinje cells en route from the external
zone is considered to be populated by a single basic type of progenitor pial layer to their final central position. Later, the final form of their
cell and to exhibit three phases. The cells show an ‘elevator movement’ projections, cell volume and, indeed, their continuing survival depend
as they pass through a complete mitotic cycle, progressively approach- on the establishment of patterns of functional connection.
ing and then receding from the internal limiting membrane, which Initially immature neurones are rotund or fusiform. Their cytoplasm
corresponds to the apical region of the radial glial cells (Fig. 17.15). contains a prominent Golgi apparatus, many lysosomes, glycogen and
DNA replication occurs while the cells are extended and their nuclei numerous unattached ribosomes. As maturation proceeds, cells send
approach the pial surface; they then enter a premitotic resting period out fine cytoplasmic processes that contain neurofilaments, microtu-
while the cells shorten and their nuclei pass back towards the ventricu- bules and other structures, often including centrioles at their bases
lar surface. The cells now become rounded close to the internal limiting where microtubules form. Internally, endoplasmic reticulum cisternae
membrane and undergo mitosis. They then elongate and their nuclei appear and attached ribosomes and mitochondria proliferate, whereas


move towards the outer edge during the postmitotic resting period, after the glycogen content progressively diminishes. One process becomes
which DNA synthesis commences once more and the cycle is repeated. the axon and other processes establish a dendritic tree. Axonal growth,
The cells so formed may then either start another proliferative cycle or studied in tissue culture, may be as much as 1 mm per day.
migrate outwards (i.e. radially) and differentiate into neurones as they Successful neuronal connectivity is the product of a series of tightly
approach and enter the adjacent stratum. This differentiation may be regulated, programmed events that include axon initiation, growth cone
initiated as they pass outwards during the postmitotic resting period. formation and navigation, formation and pruning of dendritic trees and
The proliferative cycle continues with the production of clones of neu- synapses (Chiu et al 2013).
rones and glioblasts. This sequence of events has been called inter-
kinetic nuclear migration; it eventually declines. At the last division,
Growth cones
two postmitotic daughter cells are produced and they differentiate at
the ventricular surface into ependyma.
The progeny of some of these divisions move away from the ven- During development, the growing axons of neuroblasts navigate with
tricular zone to form an intermediate zone of neurones. The early precision over considerable distances, often pursuing complex courses
spinal cord and much of the brainstem show only these three main to reach their targets. Eventually, they make functional contact with
layers, i.e. ventricular, intermediate and marginal zones. However, in their appropriate end organs (neuromuscular endings, secretomotor
the telencephalon, the region of cellular proliferation extends deeper terminals, sensory corpuscles or synapses with other neurones). Ramón
than the ventricular zone where the escalator movement of interkinetic y Cajal (1890) was the first to describe the expanded growing tips of
migration is seen, and a subventricular zone appears between the ven- axons, naming them growth cones. These tips are constantly active,
tricular and intermediate layers (see Fig. 17.15). Here, cells continue to changing shape, and extending and withdrawing small protuberances,
multiply to provide further generations of neurones and glia, which filopodia and lamellipodia that apparently ‘explore’ the local environ-


subsequently migrate into the intermediate and marginal zones. A ment for a suitable surface over which to extend. This incessant palpa-
population of cells resulting from the asymmetric division of stem cells tory activity depends on the organization and dynamics of actin
at the ventricular zone move to the subventricular zone, where they filaments that fill the growth cone leading margin (peripheral (P−)
divide symmetrically. These cells are termed intermediate neural pro- domain) and is regulated by actin-binding proteins that control all
genitor cells or basal progenitors to emphasize the fact that they are no aspects of filament assembly, turnover, interactions with other filaments
longer attached to the apical (ventricular) surface. They translocate and cytoplasmic components, and the production of mechanical forces.
their nucleus to an abventricular location for mitosis. The cells are Tbr- Adhesive ligands and extrinsic guidance cues bind growth cone recep-
2-positive and appear to migrate tangentially rather than radially in tors to their substratum and trigger signalling activities involving Rho
the developing cortex (Miyata et al 2010, Sessa et al 2010, Fietz and GTPases, kinases, phosphatases, cyclic nucleotides, and Ca2+ fluxes.
Huttner 2011). Adhesion to the substratum appears to be important for transient con-
In certain regions of the nervous system (e.g. the cerebellar cortex), solidation (stabilization) of the growth cone, elaboration of the axonal
some mitotic subventricular stem cells migrate across the entire neural cytoskeleton in the direction of growth and transduction of mechanical
wall to form a subpial population and establish a new zone of cell forces into traction in order to pull the axon towards its next target
division and differentiation. Many cells formed in this site remain (Gomez and Letourneau 2014). Following consolidation of the
subpial in position, but others migrate back towards the ventricle growth cone, the exploratory behaviour begins again, resembling the
esahp
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2G
sisotiM
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1G
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Phase of
cell cycle


mechanisms of neural development
247
71
RETPAHC
behaviour at the leading edge of migratory cells such as fibroblasts and ergic neurones. BDNF promotes the survival of retinal ganglion cells,
neutrophils. motor neurones, and some placode-derived neurones, such as those of
Axon guidance involves the coordinate action of four types of cues: the nodose ganglion, that are unresponsive to NGF. NT-3 has effects on
short-range, local cues and long-range, diffusible cues, each of which motor neurones, limb proprioceptive neurones and both placode- and
can be either positive (permissive or attractive) or negative (inhibitory neural crest-derived sensory neurones. Other growth factors found to
or repellent); mechanisms may involve contact attraction or chemo- influence the growth and survival of neural cells include the FGFs and
attraction, contact repulsion or chemorepulsion. Changes in the local ciliary neurotrophic factor (CNTF), all of which are unrelated in
proteome enable growth cones to respond rapidly to these cues by sequence to the NGF family. Members of the FGF family support the
elongating, turning or collapsing. Different axons may respond to the survival of embryonic neurones from many regions of the CNS. CNTF
same cue differently, according to the distribution of receptors or com- may control the proliferation and differentiation of sympathetic gan-
ponents of the relevant signal transduction pathways on their surfaces. glion cells and astrocytes.
Axon extension occurs when growth cones encounter a permissive, Each of the neurotrophins binds specifically to certain receptors on
physical substrate containing short-range cues such as appropriate the cell surface. The receptor termed p75NTR binds all the neurotrophins
extracellular matrix components, transmembrane phosphatases and with similar affinity. By contrast, members of the family of receptor
cadherins; axonal repulsion requires negative cues that inhibit the tyrosine kinases (Trks) bind with higher affinity and display binding
progress of the growth cone. Long-range cues diffuse from distant preferences for particular neurotrophins. However, the presence of a Trk
targets down gradients of specific factors, inducing neurones to turn receptor seems to be required for p75NTR function.


their axons either towards the source of an attractive signal or away from Nervous tissue influences the metabolism of its target tissues. If,
a repulsive signal. Topographic projections, such as the retinotectal during development, a nerve fails to connect with its muscle, both
pathway, are established as specific populations of growth cones follow degenerate. If the innervation of slow (red) or fast (white) skeletal
spatial gradients of guidance cues (see Kalil et al (2011)). muscle is exchanged, the muscles change structure and properties to
Several families of signalling molecules are known to be instructive reflect the new innervation, indicating that the nerve determines muscle
guidance cues. The original canonical group of netrins, semaphorins, type and not vice versa. Concomitant anterograde signalling by a
slits and ephrins has now been amplified by members of three families neurone to its target tissues and retrograde signalling from target tissues
of developmental morphogens (bone morphogenetic protein (BMP), to the same neurone implies instructive interactions; they occur during
Hedgehog and Wnt families) and a number of growth factors (hepato- development, postnatally and in adult life (Harris 2008, da Silva and
cyte growth factor (HGF), fibroblast growth factors (FGFs) and glial Wang 2011).
cell-derived neurotrophic factor (GDNF)) for subsets of motor axons,
neurotrophins (brain-derived neurotrophic factor (BDNF) and neuro-
INDUCTION AND PATTERNING OF THE BRAIN
trophin 3 (NT3)) for sensory axons, neuregulins for thalamocortical
axons, and vascular endothelial growth factor A (VEGFA) for commis- AND SPINAL CORD
sural axons (Kolodkin and Tessier-Lavigne 2013).
The generation of neural tissue involves an inductive signal from the
Dendritic trees and synaptogenesis underlying chordamesoderm (notochord), termed the ‘organizer’. The
observation by Spemann and Mangold in 1924 that, in intact amphib-
ian embryos, the presence of an organizer caused ectodermal cells to
Once growth cones have arrived in their appropriate target area, they
form nervous tissue, whereas in its absence they formed epidermis, led


form terminals and synapses. Extensive dendritic trees are generated
to the discovery of neural induction. However, experiments performed
and subsequently shaped by dendrite retraction and pruning. Signalling
much later in the century revealed that, when ectodermal cells were
mechanisms underlying these processes are poorly understood: centro-
dissociated, they also gave rise to neural tissue. The paradox was resolved
somal CaMKIIβ signalling has been proposed as a mechanism restrict-
by the finding that intact ectodermal tissue is prevented from becoming
ing dendrite elaboration while promoting dendrite pruning (Puram
neural by an inhibitory signal(s) that is diluted out when cells are dis-
et al 2011). The final shape of dendritic trees is influenced by patterns
sociated. Many lines of evidence now indicate that this inhibitory signal
of afferent connections and their activity, and is necessary for the accu-
is mediated by members of a family of secreted proteins, the BMPs.
rate formation of neuronal circuitry. Defects in dendrite patterning have
These molecules are found throughout ectodermal tissue during early
been implicated in the pathology of mental retardation and autism
development, and their inhibitory effect is antagonized by several
spectrum disorders.
neural inducers that are present within the organizer, i.e. noggin,
Activity-dependent stabilization, coupled with the selective elimina-
chordin and follistatin. Each of these factors is capable of blocking
tion of surplus synapses, is a key mechanism for generating diversity in
BMP signalling – in some cases, by preventing it from binding to its
neuronal connectivity. Dendritic spine density in childhood exceeds
receptor(s).
adult values by two- to three-fold and begins to decrease during puberty.
The regional pattern of the nervous system is induced before and
However, the overproduction and later pruning of supernumerary syn-
during neural tube closure. The patterning in the ventrodorsal domain
apses continues well into the third decade of life before stabilizing
is imposed on the neural plate/tube by external signals (notochord),
(Petanjek et al 2011, Kolb et al 2013). Once established, dendritic trees
whereas the longitudinal patterning is based on local expression
appear remarkably stable; partial deafferentation usually affects only
domains. Early concepts about regional patterning envisaged that
dendritic spines.


regionalization within mesenchymal populations that transmit induc-
tive signals to the ectoderm impose a similar mosaic of positional
Neurotrophins
values on the overlying neural plate. For example, transplantation of
caudal mesenchyme beneath the neural plate in amphibia induced
If neurones lose all afferent connections or are totally deprived of spinal cord, whereas rostral mesenchyme induced brain, as assessed by
sensory input, much of the dendritic tree, and even the whole soma, the morphology of the neuroepithelial vesicles. However, later work
will atrophy. Different regions of the nervous system vary quantitatively indicated a more complex scenario, in which organizer grafts from early
in their response to such anterograde transneuronal degeneration. embryos induced mainly head structures, while later grafts induced
Similar effects occur in retrograde transneuronal degeneration. Thus, mainly trunk structures. Subsequent molecular data have tended to
neurones are dependent on peripheral structures for their survival. Loss support a model in which neural-inducing factors released by the
of muscles or sensory nerve endings, e.g. in the developing limb, will organizer, such as noggin, chordin and follistatin, neuralize the ecto-
result in reduction in numbers of motor and sensory neurones. Specific derm and promote a mainly rostral neural identity. Later, secreted
factors that these target organs produce, such as the neurotrophins, are signals then act to caudalize this rostral neural tissue, setting up an
taken into nerve endings and transported back to the neuronal somata; entire array of axial values along the neural tube. Candidates for these
they are necessary for the survival of many types of neurone during early later, caudalizing, signals have been shown to be retinoic acid, FGFs
development, and for the growth of their axons and dendrites, and also and the WNT secreted proteins, which are present in the paraxial mes-
promote the synthesis of neurotransmitters and enzymes. enchyme and, later, in its derivatives, the somites. This combination of
Neurotrophins belong to several families of structurally and func- signals does not seem to be sufficient to produce the most rostral,
tionally related molecules, including nerve growth factor (NGF) super- forebrain structures. Other secreted proteins resident in the rostralmost


family and GDNF family (Cirulli and Alleva 2009, Park and Poo 2013, part of the earliest ingressing axial populations of endoderm and mes-
West et al 2014). The NGF superfamily includes BDNF, NT-3 and enchyme are also capable of inducing markers of forebrain identity
NT-4/5, which exert their survival effects selectively on particular subsets from ectodermal cells (Withington et al 2001).
of neurones. NGF is specific to sensory ganglion cells from the neural As the neural tube grows and is modified in shape, a number
crest, sympathetic postganglionic neurones and basal forebrain cholin- of mechanisms refine the crude rostrocaudal pattern that has been


DEvEloPmENT of THE NERvous sysTEm
248
3
NoITCEs
imposed during neurulation. Molecules that diffuse from tissues adja- patterning can then develop. The consequences of early segmentation
cent to the neural tube, such as the somites, have patterning influences. for events later in development, such as the formation of definitive
The neural tube possesses a number of intrinsic signalling centres, such neuronal nuclei within the brainstem, and of peripheral axonal projec-
as the midbrain–hindbrain boundary, which produce diffusible mole- tions remain to be explored.
cules capable of influencing tissue development at a distance. In this Other brain regions are not segmented in quite the same way as
way, extrinsic and intrinsic factors serve to subdivide the neural tube the hindbrain. However, morphological boundaries, domains of cell
into a number of fairly large domains, on which local influences can lineage restriction and of cell mixing, and regions of gene expression
then act. Domains are distinguished by their expression of particular that abut sharp boundaries, are found in the diencephalon and telen-
transcription factors, which, in many cases, have been causally related cephalon. It is thus likely that compartmentation of cell groups with
to the development of particular regions. Examples of such genes are some, if not all, the features of rhombomeres plays an important role
the Hox family, which are expressed in the spinal cord and hindbrain, in the formation of various brain regions.
and the Dlx, Emx and Otx families of genes, which are expressed in The significance of intrinsic segmentation in the hindbrain is under-
various regions of the forebrain. All of these are developmental control lined by the absence of overt segmentation of the adjacent paraxial
genes that lie high up in the hierarchy, and are capable of initiating mesenchyme. There is no firm evidence for intrinsic segmentation in
cascades of expression of other genes to create a more fine-grained the spinal cord. Instead, segmentation of the neural crest, motor axons
pattern of cellular differentiation. In contrast to the aforementioned and thus, eventually, the spinal nerves is dependent on the segmenta-
secreted molecules, these genes encode proteins that are retained in the tion of the neighbouring somites. Both neural crest cell migration and


cell nucleus, and so can act on DNA to induce or repress further gene motor axon outgrowth occur through only the rostral and not the
expression. caudal sclerotome of each somite, so that dorsal root ganglia form only
at intervals. The caudal sclerotome possesses inhibitory properties that
Segmentation in the neural tube deter neural crest cells and motor axons from entering. This illustrates
the general principle that the nervous system is closely interlocked, in
terms of morphogenesis, with the ‘periphery’, i.e. surrounding non-
The early neural tube is visibly divided into segments, termed neuro-
nervous structures, and each is dependent on the other for its effective
meres, by shallow transverse folds that extend perpendicular to its long
structural and functional maturation.
axis. Primary neuromeres can be identified at stage 9, and 16 secondary
Genes such as the Hox and Pax gene families, which encode tran-
neuromeres are present at stage 14. They are especially noted in the
scription factor proteins, show intriguing expression patterns within the
rhombencephalon, where they are termed rhombomeres, crucial units
nervous system. Genes of the Hox-b cluster, for example, are expressed
of pattern formation (Tümpel et al 2009). Domains of expression of
throughout the caudal neural tube, and up to discrete limits in the
developmental control genes abut rhombomere boundaries; single-cell
hindbrain that coincide with rhombomere boundaries. The ordering of
labelling experiments have revealed that cells within rhombomeres
form segregated non-mixing populations (Fig. 17.16). The neural crest
these genes within a cluster on the chromosome (5′–3′) is the same as
the caudal to rostral limits of expression of consecutive genes. This
also shows intrinsic segmentation in the rhombencephalon, and is
characteristic pattern is surprisingly similar in fish, frogs, birds and
segregated into streams at its point of origin in the dorsal neural tube.
mammals. Hox genes play a role in patterning not only of the neural
This may represent a mechanism whereby morphogenetic specification
tube but also of much of the head region, consistent with their expres-
of the premigratory neural crest cells is conveyed to the pharyngeal


sion in neural crest cells, and within the pharyngeal arches. Disruption
arches (see Fig. 12.4). Although these segmental units lose their mor-
of Hox a-3 gene in mice mimics DiGeorge’s syndrome, a congenital
phological prominence with subsequent development, they represent
human disorder characterized by the absence (or near-absence) of the
the fundamental ground plan of this part of the neuraxis, creating a
thymus, parathyroid and thyroid glands, by the hypotrophy of the walls
series of semi-autonomous units, within which local variations in
of the arteries derived from the aortic arches, and by subsequent
conotruncal cardiac malformations. Some Pax genes are expressed in
different dorsoventral domains within the neural tube. Pax-3 is expressed
r1 r2 r3 r4 r5 r6 r7 r8 Rhombomeres
in the alar lamina, including the neural crest, while Pax-6 is expressed
in the intermediate plate. The Pax-3 gene has the same chromosomal
localization as the mouse mutation Splotch and the affected locus in
the human Waardenburg’s syndrome, both of which are characterized
by neural crest disturbances with pigmentation disorders and occa-
Neural sional neural tube defects. Both Hox and Pax genes have restricted
crest cells
expression patterns with respect to the rostrocaudal and the dorsoven-
tral axes of the neural tube, consistent with roles in positional specifica-
Surface tion. (For reviews of the expression patterns of these genes, see Krumlauf
ectoderm et al (1993).)
B3 B4+ While craniocaudal positional values are probably conferred on the
B2 neuroepithelium at the neural plate or early neural tube stage, dorso-
B1 ventral positional values may become fixed later. The development of
the dorsoventral axis is heavily influenced by the presence of the under-
lying notochord. The notochord induces the ventral midline of the
Hox a
neural tube, the floor plate. This specialized region consists of a strip
a-1 a-2 a-3 a-4
of non-neural cells with distinctive adhesive and functional properties.
Notochord and floor plate together participate in inducing the differ-
Hox b entiation of the motor columns. Motor neurone differentiation occurs


b-1 b-2 b-3 b-4 early, giving some grounds for the idea of a ventral to dorsal wave of
differentiation. The notochord/floor plate complex may also be respon-
sible for allotting the values of more dorsal cell types within the tube
Hox c
(see Fig. 17.7). For example, the dorsal domain of expression of Pax-3
c-4 extends more ventrally in embryos experimentally deprived of noto-
chord and floor plate, while grafting an extra notochord adjacent to the
Hox d dorsal neural tube leads to a repression of Pax-3 expression.
d-1 d-3 d-4
Fig. 17.16 Hox gene expression domains in the branchiorhombomeric
area in the mouse embryo at E9.5. The arrows indicate neural crest cells PERIPHERAL NERVOUS SYSTEM
migrating from the rhombencephalon and midbrain. Cells migrating from
the rhombencephalon are shaded to indicate the Hox genes they express. SOMATIC NERVES
The same combination of Hox genes is expressed in the rhombomeres
and in the superficial ectoderm of the pharyngeal arches at the
Spinal nerves
corresponding rostrocaudal levels. The four Hox clusters are represented
below. (Modified with permission from the Annual Review of Cell and
Developmental Biology, Volume 8, 1992 by Annual Reviews Each spinal nerve is connected to the spinal cord by a ventral root and
www.annualreviews.org.) a dorsal root (Fig. 17.17). The fibres of the ventral roots grow out from


Peripheral nervous system
249
71
RETPAHC
A B Fasciculus gracilis Posterior (dorsal)
Fasciculus cuneatus funiculus
Roof plate Dorsolateral lamina
Posterior median septum
Dorsal column
Oval bundle of grey matter
Dorsal nerve root
Dorsal nerve root
Sensory region Central canal Sensory Lateral funiculus
region
Ependymal layer
Autonomic region
(ventricular zone) Sulcus limitans
Autonomic
Motor region Lateral funiculus region Ventral (anterior)
column of
Ventrolateral lamina grey matter
Motor region
Ventral nerve root
Central canal
Floor plate Ventral (anterior) funiculus
Ventral nerve root
Ventral median fissure Anterior funiculus
Fig. 17.17 The developing spinal cord of human embryos. Transverse sections. A, Approximately 6 weeks. B, Approximately 3 months.
Abducens nerve Facial and vestibulocochlear nerves
Trigeminal ganglion Roots of accessory nerve
Trochlear nerve
X XI
IX
VIII
V VII
Oculomotor nerve Hypoglossal nerve
XII
Glossopharyngeal nerve
Accessory nerve
Ophthalmic nerve
Telencephalon
Dorsal ganglia of
Diencephalon Olfactory bulb sixth and seventh
Mesencephalon cervical spinal nerves
Metencephalon Vagus nerve
Myelencephalon
Neural crest-derived cells Maxillary nerve
Placode-derived cells Mandibular nerve
Phrenic nerve
Fig. 17.18 The brain and cranial nerves of a human embryo, 10.2 mm long. Note the derivation of the ganglia associated with the trigeminal, facial,
vestibulocochlear, glossopharyngeal, vagus and accessory nerves.
cell bodies in the anterior and lateral parts of the intermediate zone. fusiform, and their extremities gradually elongate into central and
These pass through the overlying marginal zone and external limiting peripheral processes. The central processes grow into the neural tube as
membrane. Some enter the myotomes of the somites, and some pen- the fibres of dorsal nerve roots, while the peripheral processes grow


etrate the somites, reaching the adjacent somatopleure; in both sites, ventrolaterally to mingle with the fibres of the ventral root, thus forming
they ultimately form the α-, β- and γ-efferents. At appropriate levels, a mixed spinal nerve. As development proceeds, the original bipolar
these are accompanied by the outgrowing axons of preganglionic sym- form of the cells in the spinal ganglia changes; the two processes
pathetic neuroblasts (segments T1–L2) or preganglionic parasympa- become closer and ultimately fuse to form a single stem, producing the
thetic neuroblasts (S2–S4). characteristic morphology of a unipolar neurone. The bipolar form is
The fibres of the dorsal roots extend from cell somata in dorsal root retained in the ganglion of the vestibulocochlear nerve. For details of
ganglia into the spinal cord and also extend into the periphery. Neural the timing of spinal nerve maturation, see Ashwell and Waite (2012).
crest cells are produced continuously along the length of the spinal
cord, but gangliogenic cells migrate only into the rostral part of each
Cranial nerves
somitic sclerotome, where they condense and proliferate to form a
bilateral series of oval-shaped primordial spinal ganglia (dorsal root
ganglia) (see Fig. 17.11). Negative factors in the caudal sclerotome deter Cranial nerves may contain motor, sensory or both types of fibres. With
neural crest from entering. The rostral sclerotome has a mitogenic effect the exception of the olfactory and optic nerves, the cranial nerves
on the crest cells that settle within it. From the ventral region of each develop in a manner similar, in some respects, to components of the
ganglion, a small part separates to form sympathochromaffin cells, spinal nerves. The somata of motor neuroblasts originate within the
while the remainder becomes a definitive spinal ganglion (dorsal root neuroepithelium, while those of sensory neuroblasts are derived from
ganglion). The spinal ganglia are arranged symmetrically at the sides of the neural crest, with the addition in the head of contributions from


the neural tube and, except in the caudal region, are equal in number ectodermal placodes (Fig. 17.18; see Fig. 12.4).
to the somites. The cells of the ganglia, like the cells of the intermediate The motor fibres of the cranial nerves that project to striated muscle
zone of the early neural tube, are glial and neuronal precursors. The are the axons of cells originating in the basal plate of the midbrain and
glial precursors develop into satellite cells (which become closely hindbrain. The functional and morphological distinction between the
applied to the ganglionic nerve cell somata), Schwann cells and, pos- neurones within these various nerves is based on the types of muscle
sibly, other cells. The neuroblasts, at first round or oval, soon become innervated. In the trunk, the motor roots of the spinal nerves all emerge


DEvEloPmENT of THE NERvous sysTEm
250
3
NoITCEs
from the spinal cord close to the ventral midline to supply the muscles overgrowth, folding and subsequent fusion of tissue derived from the
derived from the somites. rhombic lip on the external aspect of the bundle.
In the head, the motor outflow is traditionally segregated into two For details of the development of sensory and cranial nerve nuclei,
pathways (see Figs 17.3B, 17.18). General somatic efferent neurones see Ashwell and Mai (2012).
exit ventrally in a similar manner to those of the spinal cord. Thus
the oculomotor, trochlear, abducens and hypoglossal nerves parallel
the organization of the somatic motor neurones in the spinal cord. The AUTONOMIC NERVOUS SYSTEM
second motor component, special branchial efferent, consists of the
motor parts of the trigeminal, facial, glossopharyngeal and vagus nerves Autonomic nerves, apart from the preganglionic motor axons arising
that supply the pharyngeal (branchial) arches, and the accessory nerve. from the CNS, are formed by the neural crest. For the purposes of the
These nerves all have nerve exit points more dorsally placed than the following description, the autonomic nervous system encompasses
somatic motor system. sympathetic and parasympathetic neurones and their accompanying
The cranial nerves also contain general visceral efferent (parasympa- glia in the peripheral ganglia, the neurones and glia of the enteric
thetic preganglionic) neurones that travel in the oculomotor, facial, nervous system, and chromaffin cells in the suprarenal medulla.
glossopharyngeal and vagus nerves, and leave the hindbrain via the In the trunk at neurulation, neural crest cells migrate from the neural
same exit points as the special branchial efferent fibres. All three catego- epithelium to lie transitorily on the fused neural tube. Thereafter, crest
ries of motor neurones probably originate from the same region of the cells migrate laterally and then ventrally to their respective destinations


basal plate, adjacent to the floor plate. The definitive arrangement of (see Fig. 17.11). Within the head, the neural crest cells migrate prior to
nuclei reflects the differential migration of neuronal somata. It is not neural fusion, producing a vast mesenchymal population as well as
known whether all these cell types share a common precursor within autonomic neurones.
the rhombencephalon; however, in the spinal cord, somatic motor and The four major regions of neural crest cell distribution to the auto-
preganglionic autonomic neurones are linearly related. nomic nervous system are cranial, vagal, trunk and lumbosacral. The
These motor neurone types have been designated according to the cranial neural crest gives rise to the cranial parasympathetic ganglia,
types of muscles or structures they innervate. General somatic efferent whereas the vagal neural crest gives rise to the thoracic parasympathetic
nerves supply striated muscle derived from the cranial (occipital) ganglia. The trunk neural crest gives rise to the sympathetic ganglia,
somites and prechordal mesenchyme. Myogenic cells from the ventro- mainly the paravertebral ganglia, and suprarenomedullary cells. This
lateral edge of the epithelial plate of occipital somites give rise to the category is often referred to as the sympathosuprarenal lineage.
intrinsic muscles of the tongue, while the prechordal mesenchyme gives Neurones of the enteric nervous system are described as arising from
rise to the extrinsic ocular muscles. Special branchial efferent nerves the vagal crest, i.e. neural crest derived from somite levels 1–7, and the
supply the striated muscles developing within the pharyngeal (branchial) sacral crest, caudal to the twenty-eighth somite. At all of these levels,
arches (see Fig. 12.4), which are derived from parachordal mesenchyme the crest cells also differentiate into glial-like support cells alongside
between the occipital somites and the prechordal mesenchyme. All the the neurones (Fig. 17.19).
voluntary muscles of the head originate from axial (prechordal) or
paraxial mesenchyme, which renders the distinction between somatic


efferent supply and branchial efferent supply somewhat artificial.
However, the obviously special nature of the arch musculature, its pat-
terning by the neural crest cells, its particularly rich innervation for both
voluntary and reflex activity, and the different origins from the basal
plate of the branchial efferent nerves compared to the somatic efferent Melanocytes
nerves make the retention of a distinction between the two of some
value.
General visceral efferent (parasympathetic preganglionic) neurones
innervate glands of the head, the thoracic and abdominal viscera, and
Otocyst
sphincter pupillae and ciliaris.
The cranial sensory ganglia are derived in part from the neural crest,
and in part from cells of the ectodermal placodes (see Figs 17.12, 17.18). 1
1 1
Generally, neurones distal to the brain are derived from placodes while 1
proximal ones are derived from the neural crest (see Fig. 17.18). Sup- Occipital 2 Enteric
Glial
porting cells of all sensory ganglia arise from the neural crest. The most cells of 3 nervous
rostral sensory ganglion, the trigeminal, contains both neural crest- and ENS 1 4 system 5 5
placode-derived neurones that mediate general somatic afferent func- 5 [ENS]
6
tions. In the case of more caudal cranial nerves (the facial, glossopha-
ryngeal and vagus), the same applies, but the two cell populations form 7 Cervical 7 7
8
separate ganglia in the case of each nerve. The proximal series of ganglia
9
is neural crest-derived (forming the proximal ganglion of the facial 10 All dorsal
nerve, the superior ganglion of the glossopharyngeal nerve and the 11 root ganglia
1
jugular ganglion of the vagus) while the distal series is derived from 12 and sensory
placodal cells (forming the geniculate ganglion of the facial nerve, the 13 nerves
petrosal ganglion of the glossopharyngeal nerve and the nodose gan- 14


glion of the vagus). These ganglia contain neurones that mediate special, 15
16
general visceral and somatic afferent functions. The vestibular ganglion
contains both crest and placodal cells, and the acoustic ganglion con- Thoracic 17 18 Sympathetic
18
tains only placodal neurones; the axons from these cells are special Schwann ganglia
somatic afferents and they all travel in the vestibulocochlear nerve. cells 1 29 0 Ch cr eo lm ls a of ffin a pn ad r an -e ar ov re tis c,
The neurones and supporting cells of the cranial autonomic ganglia 21 suprarenal ganglia
in the head and the trunk originate from neural crest cells. Caudal to 22 medulla
the vagal ganglion, the occipital region of the neural crest is concerned 23
1
with the ‘ganglia’ of the accessory and hypoglossal nerves. Rudimentary 24 24
ganglion cells may occur along the hypoglossal nerve in the human Lumbar 25
26
embryo but they subsequently regress. Ganglion cells are found on the
developing intraspinal root of the accessory nerve and are believed to 28 27 28
28
persist in the adult. The central processes of the cells of these various 1
29
ganglia, where they persist, enter the alar lamina of the hindbrain. Their Glial 30
peripheral processes join the efferent components of the nerve to be cells of Sacral 31 ENS
distributed to the various tissues innervated. Some incoming fibres ENS 32
from the facial, glossopharyngeal and vagus nerves collect to form an 33
oval bundle, the tractus solitarius, on the lateral aspect of the myelen- 34
cephalon. This bundle is the homologue of the oval bundle of the Fig. 17.19 The derivatives of neural crest cells in the trunk. The fate of
spinal cord, but in the hindbrain it becomes more deeply placed by the crest cells arising at particular somite levels is shown.


Peripheral nervous system
251
71
RETPAHC
Parasympathetic ganglia preganglionic fibres that supply the intestine, and therefore modulate
the enteric neurones, is much fewer.
The enteric nervous system is derived from the neural crest. The axial
Neural crest cells migrate from the region of the mesencephalon and
levels of crest origin are shown in Figure 17.19. Premigratory neural
rhombencephalon prior to neural tube closure. From rostral to caudal,
crest cells are not pre-patterned for specific axial levels; rather, they
three populations of neural crest have been noted: cranial neural crest,
attain their axial value as they leave the neuraxis. Once within the gut
cardiac neural crest and vagal neural crest. The migration of the sacral
wall, there is a regionally specific pattern of enteric ganglia formation,
neural crest and the formation of the caudal parasympathetic ganglia
which may be controlled by the local splanchnopleuric mesenchyme.
have attracted little research interest.
Cranial neural crest from somite levels 1–7 contributes to the enteric
Neural crest cells from the caudal third of the mesencephalon and
nervous system, forming both neuroblasts and glial support cells.
the rostral metencephalon migrate along or close to the ophthalmic
The most caudal derivatives of neural crest cells, from the lumbosac-
branch of the trigeminal nerve and give rise to the ciliary ganglion.
ral region, somites 28 onwards, form components of the pelvic plexus
Cells migrating from the nucleus of the oculomotor nerve may also
after migrating through the somites towards the level of the colon,
contribute to the ganglion; a few scattered cells are always demonstra-
rectum and cloaca. Initially, the cells come to lie within the developing
ble in postnatal life along the course of this nerve. Preotic myelen-
mesentery, then transiently between the layers of the differentiating cephalic neural crest cells give rise to the pterygopalatine ganglion,
muscularis externa, before finally forming a more substantial intramu-
which may also receive contributions from the ganglia of the trigemi-


ral plexus characteristic of the adult enteric nervous system. The gut has nal and facial nerves. The otic and submandibular ganglia are also
a partially established enteric nervous system with a full complement
derived from myelencephalic neural crest and may receive contribu-
of enteric neurotransmitters by 24 weeks. Maturation continues into the
tions from the glossopharyngeal and facial cranial nerves, respectively
postnatal period (Ashwell and Waite 2012).
(see Fig. 12.4).
Hirschsprung’s disease appears to result from a failure of neural crest
Neural crest from the region located between the otic placode and
cells to colonize the gut wall appropriately. The rectum is always affected
the caudal limit of somite 3 has been termed cardiac neural crest. Cells
and the proximal extent of the condition is variable. The condition is
derived from these levels migrate through pharyngeal arches 3, 4 and
characterized by a dilated segment of colon proximally (or small bowel
6, where they provide, inter alia, support for the embryonic aortic arch
in cases of total colonic Hirschsprung’s disease) and lack of peristalsis
arteries, cells of the aorticopulmonary septum and truncus arteriosus.
in the segment distal to the dilation. The condition is also characterized
Some of these neural crest cells also differentiate into the neural anlage
by a transition zone with reduced innervation. It is important to be
of the parasympathetic ganglia of the heart. Sensory innervation of the
aware that the transition zone may follow an asymmetric course around
heart is from the inferior ganglion of the vagus, which is derived from
the circumference of the bowel and a single biopsy may be unreliable.
the nodose placodes. Neural crest cells migrating from the level of
Neonates with Hirschsprung’s disease show delay in the passage of
somites 1–7 are collectively termed vagal neural crest; they migrate to
meconium, constipation, vomiting and abdominal distension. In
the gut along with sacral neural crest.
humans, Hirschsprung’s disease is often seen associated with other
defects of neural crest development, e.g. Waardenburg type II syndrome,
Sympathetic ganglia


which includes deafness and facial clefts with megacolon.
Of the neural crest cells that colonize the bowel, some in the foregut
Neural crest cells migrate ventrally within the body segments, penetrate
may acquire the ability to migrate outwards and colonize the develop-
the underlying somites and continue to the region of the future para-
ing pancreas.
vertebral and prevertebral plexuses, where they form the sympathetic
chain of ganglia and the major ganglia around the ventral visceral
branches of the abdominal aorta (see Figs 17.11, 17.19). Neural crest Chromaffin cells
cells are induced to differentiate into sympathetic neurones by the
dorsal aorta through the actions of the signalling molecules Bmp-4 and Chromaffin cells are derived from the neural crest and found at numer-
Bmp-7. The sympathetic trunk can be seen in the lower cervical and ous sites throughout the body. They are the classic chromaffin cells of
thoracic regions by 4–5 weeks, and the sympathetic outflow from the the suprarenal medulla, bronchial neuroepithelial cells, dispersed epi-
lumbosacral sympathetic trunk to the sciatic nerve between 18 and thelial endocrine cells of the gut (formerly known as argentaffin cells),
21 weeks (Ashwell and Waite 2012). carotid body cells, and the paraganglia (Ch. 16).
There is cell-specific recognition of postganglionic neurones and the The sympathetic ganglia, suprarenal medulla and chromaffin cells
growth cones of sympathetic preganglionic neurones. They meet during are all derived from the cells of the sympathosuprarenal lineage. In the
their growth, and this may be important in guidance to their appropri- suprarenal medulla, these cells differentiate into a number of types
ate target. The position of postganglionic neurones, and the exit point consisting of small and intermediate-sized neuroblasts or sympatho-
from the spinal cord of preganglionic neurones, may influence the types blasts, and larger, initially rounded phaeochromocytoblasts.
of synaptic connections made, and the affinity for particular postgan- Large cells with pale nuclei, thought to be the progenitors of chro-


glionic neurones. When a postganglionic neuroblast is in place, it maffin cells, can be detected from 9 weeks in human fetuses, and clus-
extends axons and dendrites, and synaptogenesis occurs. The earliest ters of small neurones are evident from 14 weeks.
axonal outgrowths from the superior cervical ganglion occur at about Intermediate-sized neuroblasts differentiate into the typical multi-
stage 14; although the axon is the first cell process to appear, the posi- polar postganglionic sympathetic neurones (which secrete noradrena-
tion of the neurones does not apparently influence the appearance of line (norepinephrine) at their terminals) of classic autonomic
the cell processes. neuroanatomy. The smaller neuroblasts have been equated with the
The local environment plays a major role in controlling the appro- small, intensely fluorescent (SIF) cells, types I and II, which store
priate differentiation of the presumptive autonomic ganglion neurones. and secrete dopamine type I and are thought to function as true in-
The identity of the factors responsible for subsequent adrenergic, terneurones, synapsing with the principal postganglionic neurones.
cholinergic or peptidergic phenotype has yet to be elucidated; it has Type II cells probably operate as local neuroendocrine cells, secreting
been proposed that fibronectin and basal lamina components initiate dopamine into the ganglionic microcirculation. Both types of SIF cells
adrenergic phenotypic expression at the expense of melanocyte num- can modulate preganglionic/postganglionic synaptic transmission in
bers. Cholinergic characteristics are acquired relatively early and the the ganglionic neurones. The large cells differentiate into masses of
appropriate phenotypic expression may be promoted by cholinergic columnar or polyhedral phaeochromocytes (classic chromaffin cells),
differentiation factor and ciliary neurotrophic factor. which secrete either adrenaline (epinephrine) or noradrenaline (nor-
Neuropeptides are expressed by autonomic neurones in vitro and epinephrine). These cell masses are termed paraganglia and may be
may be stimulated by various target tissue factors in sympathetic and situated near, on the surface of, or embedded in, the capsules of the


parasympathetic neurones. Some neuropeptides are expressed more ganglia of the sympathetic chain, or in some of the large autonomic
intensely during early stages of ganglion formation. plexuses. The largest members of the latter are the para-aortic bodies
that lie along the sides of the abdominal aorta in relation to the infe-
Enteric nervous system
rior mesenteric artery. During childhood, the para-aortic bodies and
the paraganglia of the sympathetic chain partly degenerate and can no
The enteric nervous system is different from the other components of longer be isolated by gross dissection, but even in the adult, chromaf-
the autonomic nervous system because it can mediate reflex activity fin tissue can still be recognized microscopically in these various sites.
independently of control by the brain and spinal cord. The number of Both phaeochromocytes and SIF cells belong to the amine precursor
enteric neurones that develop is believed to be of the same magnitude uptake and decarboxylation (APUD) series of cells and are paraneuro-
as the number of neurones in the spinal cord, whereas the number of nal in nature.


DEvEloPmENT of THE NERvous sysTEm
252
3
NoITCEs
many migrate to their final positions from the dorsolateral lamina (alar
CENTRAL NERVOUS SYSTEM
plate).
In the human embryo, the definitive grouping of the ventral column
SPINAL CORD cells, which characterizes the mature cord, occurs early; by the four-
teenth week (80 mm), all the major groups can be recognized. As the
In the future spinal cord, the median roof plate (dorsal lamina) anterior and lateral grey columns assume their final form, the germinal
and floor plate (ventral lamina) of the neural tube do not participate cells in the ventral part of the ventricular zone gradually stop dividing.
in the cellular proliferation that occurs in the lateral walls and so The layer becomes reduced in thickness until, ultimately, it forms the
remain thin. Their cells contribute largely to the formation of the single-layered ependyma that lines the ventral part of the central canal
ependyma. of the spinal cord.
The neuroblasts of the lateral walls of the tube are large and, at first,
round or oval (apolar). Soon, they develop processes at opposite poles Posterior (dorsal) grey column
and become bipolar neurones. However, one process is withdrawn and
the neuroblast becomes unipolar, although this is not invariably so in
The posterior (dorsal) column develops later; consequently, the
the case of the spinal cord. Further differentiation leads to the develop-
ventricular zone is, for a time, much thicker in the dorsolateral lamina
ment of dendritic processes and the cells become typical multipolar
(alar plate) than it is in the ventrolateral lamina (basal plate) (see
neurones. In the developing cord, they occur in small clusters represent-
Figs 17.6, 17.17A).
ing clones of neurones. The development of a longitudinal sulcus limi-
While the columns of grey matter are being defined, the dorsal
tans on each side of the central canal of the cord divides the ventricular
region of the central canal becomes narrow and slit-like, and its walls
and intermediate zones in each lateral wall into a basal (ventrolateral)
come into apposition and fuse with each other (see Fig. 17.17). In this


plate or lamina, and an alar (dorsolateral) plate or lamina (see Fig.
way, the central canal becomes relatively reduced in size and somewhat
17.17). This separation indicates a fundamental functional difference.
triangular in outline.
Neural precursors in the basal plate include the motor cells of the
At about the end of the fourth week, advancing axonal sprouts
anterior (ventral) and lateral grey columns, while those of the alar plate
invade the marginal zone. The first to develop are those destined to
exclusively form ‘interneurones’ (which possess both short and long
become short intersegmental fibres from the neuroblasts in the inter-
axons), some of which receive the terminals of primary sensory neu-
mediate zone, and fibres of dorsal roots of spinal nerves that pass into
rones. Caudally, the central canal of the cord ends as a fusiform dilation,
the spinal cord from neuroblasts of the early spinal ganglia. The earlier
the terminal ventricle.
dorsal root fibres that invade the dorsal marginal zone arise from small
dorsal root ganglionic neuroblasts. By the sixth week, they form a well-
Anterior (ventral) grey column
defined oval bundle near the peripheral part of the dorsolateral lamina
(see Figs 17.6–17.7A). This bundle increases in size and, spreading
The cells of the ventricular zone are closely packed at this stage and towards the median plane, forms the primitive posterior funiculus of
arranged in radial columns (see Fig. 17.6). Their disposition may be fine calibre. Later, fibres derived from new populations of large dorsal
determined in part by contact guidance along the earliest radial array root ganglionic neuroblasts join the dorsal root; they are destined to
of glial fibres that cross the full thickness of the early neuroepithelium. become fibres of much larger calibre. As the posterior funiculi increase
The cells of the intermediate zone are more loosely packed. They in thickness, their medial surfaces come into contact, separated only by
increase in number initially in the region of the basal plate. This the posterior medial septum, which is ependymal in origin and neuro-
enlargement outlines the anterior (ventral) column of the grey matter glial in nature. It is thought that the displaced primitive posterior funic-


and causes a ventral projection on each side of the median plane; the ulus may form the basis of the dorsolateral tract or fasciculus (of
floor plate remains at the bottom of the shallow groove so produced. Lissauer).
As growth proceeds, these enlargements, which are further increased by
the development of the anterior funiculi (tracts of axons passing to Maturation of the spinal cord
and from the brain), encroach on the groove until it becomes con-
verted into the slit-like anterior median fissure of the adult spinal cord.
Long intersegmental fibres begin to appear at about the third month
The axons of some of the neuroblasts in the anterior grey column cross
and corticospinal fibres are seen at about the fifth month. All nerve
the marginal zone and emerge as bundles of ventral spinal nerve root-
fibres at first lack myelin sheaths. Myelination starts in different groups
lets on the anterolateral aspect of the spinal cord. These constitute,
at different times, e.g. the ventral and dorsal nerve roots at about the
eventually, both the α-efferents that establish motor end-plates on
fifth month, the corticospinal fibres after the ninth month. In periph-
extrafusal striated muscle fibres and the γ-efferents that innervate the
eral nerves, the myelin is formed by Schwann cells (derived from neural
contractile polar regions of the intrafusal muscle fibres of the muscle
crest cells), and in the CNS by oligodendrocytes (which develop from
spindles.
the ventricular zone of the neural tube). Myelination persists until
overall growth of the CNS and PNS has ceased. In many sites, slow
Lateral grey column growth continues for long periods, even into the postpubertal years. The
cervical and lumbar enlargements appear at the time of the develop-
In the thoracic and upper lumbar regions, some intermediate zone ment of their respective limb buds.
neuroblasts in the dorsal part of the basal plate outline a lateral column.
Their axons join the emerging ventral nerve roots and pass as pregan- Ascent of conus medullaris
glionic fibres to the ganglia of the sympathetic trunk or related ganglia, In early embryonic life, the spinal cord occupies the entire length of the


the majority eventually myelinating to form white rami communi- vertebral canal, and the spinal nerves pass at right angles to the cord.
cantes. The axons within the rami synapse on the autonomic ganglionic From the second trimester, the vertebral column grows more rapidly
neurones, and axons of some of the latter pass as postganglionic fibres than the spinal cord; the relationship between the conus medullaris and
to innervate smooth muscle cells, adipose tissue or glandular cells. the vertebral column therefore changes as the conus gradually ascends
Other preganglionic sympathetic efferent axons pass to the cells of the to lie at higher vertebral levels (Barson 1970). Most of this relative
suprarenal medulla. An autonomic lateral column is also laid down in rostral migration occurs during the first half of intrauterine life. By the
the mid-sacral region. It gives origin to the preganglionic parasympa- twenty-fifth week, the terminal ventricle of the spinal cord has altered
thetic fibres that run in the pelvic splanchnic nerves. in level from the second coccygeal vertebra to the third lumbar, a dis-
The anterior region of each basal plate initially forms a continuous tance of nine segments. As the change in level begins rostrally, the
column of cells throughout the length of the developing cord. This soon caudal end of the terminal ventricle, which is adherent to the overlying
develops into two columns (on each side): one is medially placed and ectoderm, remains in situ, and the walls of the intermediate part of the
concerned with innervation of axial musculature, and the other is later- ventricle and its covering pia mater become drawn out to form a delicate
ally placed and innervates the limbs. At limb levels, the lateral column filament, the filum terminale. The separated portion of the terminal
enlarges enormously, but regresses at other levels. ventricle persists for a time, but it usually disappears before birth. It
Axons arising from ventral horn neurones, i.e. α-, β- and γ-efferent does, however, occasionally give rise to congenital cysts in the neigh-


fibres, are accompanied at thoracic, upper lumbar and midsacral levels bourhood of the coccyx. In the definitive state, the upper cervical spinal
by preganglionic autonomic efferents from neuroblasts of the develop- nerves retain their position roughly at right angles to the cord. Proceed-
ing lateral horn. Numerous interneurones develop in these sites (includ- ing caudally, the nerve roots lengthen and become progressively more
ing Renshaw cells); it is uncertain how many of these differentiate oblique. By full term (40 weeks), the conus medullaris lies between the
directly from ventrolateral lamina (basal plate) neuroblasts and how first and third lumbar vertebrae.


Central nervous system
253
71
RETPAHC
Determining the prenatal position of the conus medullaris relative constrictions of the rhombomere boundaries disappear, and the
to specific vertebrae is a widely used method of identifying the termina- medulla once again assumes a smooth contour. The differentiation of
tion of the spinal cord. Studies of formalin fixed foetuses, usually of the lateral walls of the hindbrain into basal (ventrolateral) and alar
preterm stillbirths that may be small for dates, have provided the main (dorsolateral) plates has a similar significance to the corresponding
timescales; more recently, values have been derived from antenatal differentiation in the lateral wall of the spinal cord, and ventricular,
ultrasound and magnetic resonance imaging (MRI) examinations. The intermediate and marginal zones are formed in the same way.
often wide discrepancies between published values attest to the fact that
Cells of the basal plate (ventrolateral lamina)
ageing preterm infants remains an inexact science. Measurements may
be influenced by factors such as placental health, maternal diet, ethnic Cells of the basal plate form three elongated, discontinuous, columns
biometrical variation, fetal sex, and the interpretation and correlation that are positioned ventrally and dorsally with an intermediate column
of results obtained using differing methodologies (cadaveric dissection, between (Fig. 17.20).
ultrasound, MRI). The most ventral column is continuous with the anterior grey
column of the spinal cord and will supply muscles considered ‘myo-
tomic’ in origin. It is represented in the caudal part of the hindbrain by
BRAIN the hypoglossal nucleus, and it reappears at a higher level as the nuclei
of the abducens, trochlear and oculomotor nerves (somatic efferent
A summary of the derivatives of the cerebral regions from caudal to nuclei). The intermediate column is represented in the upper part of
rostral is given in Table 17.1. the spinal cord and caudal brainstem (medulla oblongata and pons),
and its neurones supply branchial (pharyngeal) and postbranchial mus-
Rhombencephalon culature. It is discontinuous, forming the elongated nucleus ambiguus
in the caudal brainstem, which gives fibres to the ninth, tenth and


By the time the midbrain flexure appears, the length of the rhomben- eleventh cranial nerves, and continues into the cervical spinal cord as
cephalon is greater than that of the combined extent of the mesen- the origin of the accessory nerve. At higher levels, parts of this column
cephalon and prosencephalon. Rostrally, it exhibits a constriction, the give origin to the motor nuclei of the facial and trigeminal nerves. The
isthmus rhombencephali (see Fig. 17.3B), best viewed from the dorsal nucleus ambiguus and the facial and trigeminal motor nuclei are
aspect. Ventrally, the hindbrain is separated from the dorsal wall of the termed branchial (special visceral) efferent nuclei. Neurones in the
primitive pharynx only by the notochord, the two dorsal aortae and a most dorsal column of the basal plate (represented in the spinal cord
small amount of mesenchyme; on each side, it is closely related to the by the lateral grey column) innervate viscera. The column is discontinu-
dorsal ends of the pharyngeal arches. ous; its large caudal part forms some of the dorsal nucleus of the vagus
The pontine flexure appears to ‘stretch’ the thin, epithelial roof plate, and its cranial part forms the salivatory nucleus. These nuclei are termed
which becomes widened. The greatest increase in width corresponds to general visceral (general splanchnic) efferent nuclei, and their neurones
the region of maximum convexity, so that the outline of the roof plate give rise to preganglionic, parasympathetic nerve fibres.
becomes rhomboidal. By the same change, the lateral walls become It is important to note that the neurones of the basal plate and their
separated, particularly dorsally, and the cavity of the hindbrain, subse- three columnar derivatives are only motor in the sense that some of
quently the fourth ventricle, becomes flattened and somewhat triangu- their number form either motor neurones or preganglionic parasympa-
lar in cross-section. The pontine flexure becomes increasingly acute thetic neurones. The remainder, which greatly outnumber the former,


until, at the end of the second month, the laminae of its cranial (meten- differentiate into functionally related interneurones and, in some loci,
cephalic) and caudal (myelencephalic) slopes are opposed to each other into neuroendocrine cells.
(see Fig. 17.21); at the same time, the lateral angles of the cavity extend
Cell columns of the alar plate
to form the lateral recesses of the fourth ventricle.
(dorsolateral lamina)
At about 41 weeks of development, when the pontine flexure is first
2
discernible, the association between the rhombomeres and the underly- Cell columns of the alar plate are discontinuous and give rise to general
ing motor nuclei of certain cranial nerves can be seen. The general visceral (general splanchnic) afferent, special visceral (special splanch-
pattern of distribution of motor nuclei is as follows: rhombomere 1 nic) afferent, general somatic afferent, and special somatic afferent
contains the trochlear nucleus, rhombomeres 2 and 3 contain the nuclei (their relative positions, in simplified transverse section, are
trigeminal nucleus, rhombomeres 4 and 5 contain the facial nucleus, shown in Fig. 17.20). The general visceral afferent column is represented
rhombomere 5 contains the abducens nucleus, rhombomeres 6 and 7 by a part of the dorsal nucleus of the vagus, the special visceral afferent
contain the glossopharyngeal nucleus, and rhombomeres 7 and 8 column by the nucleus of the tractus solitarius, the general somatic
contain the vagal, accessory and hypoglossal nuclei. Rhombomeric seg- afferent column by the afferent nuclei of the trigeminal nerve, and the
mentation represents the ground plan of development in this region of special somatic afferent column by the nuclei of the vestibulocochlear
the brainstem and is pivotal for the development of regional identity nerve. (The relatively simple functional independence of these afferent
(see Fig. 12.4). However, with further morphogenesis, the obvious columns implied by the foregoing classification is, in the main, an aid