development of the nervous system development of the nervous system the development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. the field of neural development draws on both neuroscience and developmental biology to describe and provide insight into the cellular and molecular mechanisms by which complex nervous systems develop, from nematodes and fruit flies to mammals. this article is about neural development in all types of animals, including humans. for information specific to the human nervous system, see development of the nervous system in humans. for formation and stabilization of synapses during development, see synaptic stabilization. "neural development" redirects here. for the journal, see neural development (journal). this article is part of a series on thedevelopment of organ systems nervous systemdigestive systemreproductive systemurinary systemendocrine systemhuman developmentcirculatory system defects in neural development can lead to malformations such as holoprosencephaly, and a wide variety of neurological disorders including limb paresis and paralysis, balance and vision disorders, and seizures, and in humans other disorders such as rett syndrome, down syndrome and intellectual disability. overview of vertebrate brain development diagram of the vertebrate nervous system further information: development of the nervous system in humans the vertebrate central nervous system (cns) is derived from the ectoderm—the outermost germ layer of the embryo. a part of the dorsal ectoderm becomes specified to neural ectoderm – neuroectoderm that forms the neural plate along the dorsal side of the embryo. this is a part of the early patterning of the embryo (including the invertebrate embryo) that also establishes an anterior-posterior axis. the neural plate is the source of the majority of neurons and glial cells of the cns. the neural groove forms along the long axis of the neural plate, and the neural plate folds to give rise to the neural tube. when the tube is closed at both ends it is filled with embryonic cerebrospinal fluid. as the embryo develops, the anterior part of the neural tube expands and forms three primary brain vesicles, which become the forebrain (prosencephalon), midbrain (mesencephalon), and hindbrain (rhombencephalon). these simple, early vesicles enlarge and further divide into the telencephalon (future cerebral cortex and basal ganglia), diencephalon (future thalamus and hypothalamus), mesencephalon (future colliculi), metencephalon (future pons and cerebellum), and myelencephalon (future medulla). the csf-filled central chamber is continuous from the telencephalon to the central canal of the spinal cord, and constitutes the developing ventricular system of the cns. embryonic cerebrospinal fluid differs from that formed in later developmental stages, and from adult csf; it influences the behavior of neural precursors. because the neural tube gives rise to the brain and spinal cord any mutations at this stage in development can lead to fatal deformities like anencephaly or lifelong disabilities like spina bifida. during this time, the walls of the neural tube contain neural stem cells, which drive brain growth as they divide many times. gradually some of the cells stop dividing and differentiate into neurons and glial cells, which are the main cellular components of the cns. the newly generated neurons migrate to different parts of the developing brain to self-organize into different brain structures. once the neurons have reached their regional positions, they extend axons and dendrites, which allow them to communicate with other neurons via synapses. synaptic communication between neurons leads to the establishment of functional neural circuits that mediate sensory and motor processing, and underlie behavior. flowchart of human brain development aspects some landmarks of neural development include the birth and differentiation of neurons from stem cell precursors, the migration of immature neurons from their birthplaces in the embryo to their final positions, outgrowth of axons and dendrites from neurons, guidance of the motile growth cone through the embryo towards postsynaptic partners, the generation of synapses between these axons and their postsynaptic partners, and finally the lifelong changes in synapses, which are thought to underlie learning and memory. typically, these neurodevelopmental processes can be broadly divided into two classes: activity-independent mechanisms and activity-dependent mechanisms. activity-independent mechanisms are generally believed to occur as hardwired processes determined by genetic programs played out within individual neurons. these include differentiation, migration and axon guidance to their initial target areas. these processes are thought of as being independent of neural activity and sensory experience. once axons reach their target areas, activity-dependent mechanisms come into play. although synapse formation is an activity-independent event, modification of synapses and synapse elimination requires neural activity. developmental neuroscience uses a variety of animal models including the mouse mus musculus, the fruit fly drosophila melanogaster, the zebrafish danio rerio, the frog xenopus laevis, and the roundworm caenorhabditis elegans. myelination, formation of the lipid myelin sheath around neuronal axons, is a process that is essential for normal brain function. the myelin sheath provides insulation for the nerve impulse when communicating between neural systems. without it, the impulse would be disrupted and the signal would not reach its target, thus impairing normal functioning. because so much of brain development occurs in the prenatal stage and infancy, it is crucial that myelination, along with cortical development occur properly. magnetic resonance imaging (mri) is a non-invasive technique used to investigate myelination and cortical maturation (the cortex is the outer layer of the brain composed of gray matter). rather than showing the actual myelin, the mri picks up on the myelin water fraction, a measure of myelin content. multicomponent relaxometry (mcr) allow visualization and quantification of myelin content. mcr is also useful for tracking white matter maturation, which plays an important role in cognitive development. it has been discovered that in infancy, myelination occurs in a caudal–cranial, posterior-to-anterior pattern. because there is little evidence of a relationship between myelination and cortical thickness, it was revealed that cortical thickness is independent of white matter. this allows various aspects of the brain to grow simultaneously, leading to a more fully developed brain. neural induction during early embryonic development of the vertebrate, the dorsal ectoderm becomes specified to give rise to the epidermis and the nervous system; a part of the dorsal ectoderm becomes specified to neural ectoderm to form the neural plate which gives rise to the nervous system. the conversion of undifferentiated ectoderm to neuroectoderm requires signals from the mesoderm. at the onset of gastrulation presumptive mesodermal cells move through the dorsal blastopore lip and form a layer of mesoderm in between the endoderm and the ectoderm. mesodermal cells migrate along the dorsal midline to give rise to the notochord that develops into the vertebral column. neuroectoderm overlying the notochord develops into the neural plate in response to a diffusible signal produced by the notochord. the remainder of the ectoderm gives rise to the epidermis. the ability of the mesoderm to convert the overlying ectoderm into neural tissue is called neural induction. in the early embryo, the neural plate folds outwards to form the neural groove. beginning in the future neck region, the neural folds of this groove close to create the neural tube. the formation of the neural tube from the ectoderm is called neurulation. the ventral part of the neural tube is called the basal plate; the dorsal part is called the alar plate. the hollow interior is called the neural canal, and the open ends of the neural tube, called the neuropores, close off. a transplanted blastopore lip can convert ectoderm into neural tissue and is said to have an inductive effect. neural inducers are molecules that can induce the expression of neural genes in ectoderm explants without inducing mesodermal genes as well. neural induction is often studied in xenopus embryos since they have a simple body plan and there are good markers to distinguish between neural and non-neural tissue. examples of neural inducers are the molecules noggin and chordin. when embryonic ectodermal cells are cultured at low density in the absence of mesodermal cells they undergo neural differentiation (express neural genes), suggesting that neural differentiation is the default fate of ectodermal cells. in explant cultures (which allow direct cell-cell interactions) the same cells differentiate into epidermis. this is due to the action of bmp4 (a tgf-β family protein) that induces ectodermal cultures to differentiate into epidermis. during neural induction, noggin and chordin are produced by the dorsal mesoderm (notochord) and diffuse into the overlying ectoderm to inhibit the activity of bmp4. this inhibition of bmp4 causes the cells to differentiate into neural cells. inhibition of tgf-β and bmp (bone morphogenetic protein) signaling can efficiently induce neural tissue from pluripotent stem cells. regionalization in a later stage of development the superior part of the neural tube flexes at the level of the future midbrain—the mesencephalon, at the mesencephalic flexure or cephalic flexure. above the mesencephalon is the prosencephalon (future forebrain) and beneath it is the rhombencephalon (future hindbrain). the alar plate of the prosencephalon expands to form the telencephalon which gives rise to the cerebral hemispheres, whilst its basal plate becomes the diencephalon. the optical vesicle (which eventually become the optic nerve, retina and iris) forms at the basal plate of the prosencephalon. patterning of the nervous system in chordates, dorsal ectoderm forms all neural tissue and the nervous system. patterning occurs due to specific environmental conditions - different concentrations of signaling molecules dorsoventral axis the ventral half of the neural plate is controlled by the notochord, which acts as the 'organiser'. the dorsal half is controlled by the ectoderm plate, which flanks either side of the neural plate. ectoderm follows a default pathway to become neural tissue. evidence for this comes from single, cultured cells of ectoderm, which go on to form neural tissue. this is postulated to be because of a lack of bmps, which are blocked by the organiser. the organiser may produce molecules such as follistatin, noggin and chordin that inhibit bmps. the ventral neural tube is patterned by sonic hedgehog (shh) from the notochord, which acts as the inducing tissue. notochord-derived shh signals to the floor plate, and induces shh expression in the floor plate. floor plate-derived shh subsequently signals to other cells in the neural tube, and is essential for proper specification of ventral neuron progenitor domains. loss of shh from the notochord and/or floor plate prevents proper specification of these progenitor domains. shh binds patched1, relieving patched-mediated inhibition of smoothened, leading to activation of the gli family of transcription factors (gli1, gli2, and gli3). in this context shh acts as a morphogen - it induces cell differentiation dependent on its concentration. at low concentrations it forms ventral interneurons, at higher concentrations it induces motor neuron development, and at highest concentrations it induces floor plate differentiation. failure of shh-modulated differentiation causes holoprosencephaly. the dorsal neural tube is patterned by bmps from the epidermal ectoderm flanking the neural plate. these induce sensory interneurons by activating sr/thr kinases and altering smad transcription factor levels. rostrocaudal (anteroposterior) axis signals that control anteroposterior neural development include fgf and retinoic acid, which act in the hindbrain and spinal cord. the hindbrain, for example, is patterned by hox genes, which are expressed in overlapping domains along the anteroposterior axis under the control of retinoic acid. the 3′ (3 prime end) genes in the hox cluster are induced by retinoic acid in the hindbrain, whereas the 5′ (5 prime end) hox genes are not induced by retinoic acid and are expressed more posteriorly in the spinal cord. hoxb-1 is expressed in rhombomere 4 and gives rise to the facial nerve. without this hoxb-1 expression, a nerve similar to the trigeminal nerve arises. neurogenesis neurogenesis is the process by which neurons are generated from neural stem cells and progenitor cells. neurons are 'post-mitotic', meaning that they will never divide again for the lifetime of the organism. epigenetic modifications play a key role in regulating gene expression in differentiating neural stem cells and are critical for cell fate determination in the developing and adult mammalian brain. epigenetic modifications include dna cytosine methylation to form 5-methylcytosine and 5-methylcytosine demethylation. dna cytosine methylation is catalyzed by dna methyltransferases (dnmts). methylcytosine demethylation is catalyzed in several sequential steps by tet enzymes that carry out oxidative reactions (e.g. 5-methylcytosine to 5-hydroxymethylcytosine) and enzymes of the dna base excision repair (ber) pathway. neuronal migration corticogenesis: younger neurons migrate past older ones using radial glia as