congenital anomalies of the kidney and urinary tract ( cakut ) form a group of heterogeneous disorders that affect the kidneys , ureters and bladder . in this group
are included common problems such as vesicoureteral reflux to severe life - threatening malformations as bilateral renal agenesis [ 1 - 4 ] . in young children , cakut are the main cause of end - stage kidney disease , leading to the need for kidney transplantation or dialysis , causing major impact on growth , maturation , and disturbed cognitive development and leading to a poor life expectancy [ 5 , 6 ] . the survival rate of this group is 30 times lower than that of healthy children .
it may be also associated with kidney problems in latter life , such as hypertension and proteinuria .
cakut has also a significant economic impact on health care systems because of the patients lifelong costly therapeutic needs and impact of the employment potential of affected individuals and their families .
they are present in 0.5 to 0.6% of gestations [ 1 , 3 , 8 , 9 ] , accounting for 20 to 30% of all congenital anomalies detected in the neonatal period [ 3 , 10 , 11 ] .
this is a group diseases with an inherited polygenic trait , in addition to variable and incomplete penetrance , of multifactorial order , and can be related to de novo mutations , exposure to teratogenic substances , and maternal diet .
the development of the urinary tract depends on a series of complex events derived from several genic products ( transcription factors , growthfactors , receptors ) necessary to the distinct stages of organogenesis .
recent progresses in the understanding of the origins of urinary tract development in mice and other animals suggest a new picture to the interpretation of these defects in humans [ 3 , 14 ] .
genetic manipulations in mice identified a number of genes and genes network that direct the normal development of kidney and urinary tract , providing a new insight into the pathogenesis of cakut [ 1 , 3 , 15 - 17 ] . a list of these can be found in a database available online ( www.gudmap.org , www.omin.org ) .
the mechanistic basis for cakut associated with altered intra - uterine environment remains to be elucidated further .
maternal history of use of alcohol and drugs ( cocaine ) during pregnancy is related to the occurrence of cakut [ 18 , 19 ] .
a low - protein maternal diet during early pregnancy in mice could affect the expression of renal developmental genes ( rdg ) in the embryonic metanephros , reducing nephron number and causing renal hypoplasia .
two different mechanisms could be involved in this : low- protein levels lead to increase concentration of glucocorticoids via down - regulation of the placental steroid- metabolizing enzyme 11-hydroxysteroid dehydrogenase type2 , or causes down - regulation of angiotensin ii contents in the embryonic kidney [ 20 , 21 ] .
both excessively high and low maternal sodium intake during pregnancy in the rat cause aberrant expression of critical rdgs and reduce the final number of glomeruli in the off - spring , predisposing to hypertension later in life .
rats with deficiency of bradykinin b2 receptor exposed to an excessive sodium intake during gestation develop kidney hypodisplasia , demonstrating the principle that environmental factors may act together with mutations of a single gene in the genesis of cakut .
recent studies [ 1 , 3 , 4 , 11 - 13 , 20 - 22 ] have also steps and cause a broad phenotypic of cakut [ 1 , 3 , 24 ] proved that the very same genes responsible for the initial syndromic forms of cakut occur in the context formation of urinary tract organs would also regulate later of multiorgan malformation ( outside urogenital system ) phases of the process , explaining the broad spectrum of [ 1 , 2 ] .
genetic causes have been identified for the syndromic existing cakut , as well as different bilateral manifestations forms and have shed some light into the molecular in a same individual .
( table 1 ) . the action of different mechanisms of kidney development in human beings .
genes in kidney development with inducing effects in 10% of patients with syndromic cakut will carry dna various tissues , such mesenchyme , ureteric bud and cloaca , micro imbalances , and four chromosomal regions acting in different ontogenic stages is necessary for normal presumably associated with the cakut phenotype were morphogenesis of kidney and urinary tract .
a single identified : 1q21.1 , 2q37 , 1-q37.3 , 3q23-q25.1 and 7q36.2- gene mutation might affect kidney development at multiple q36.3 .
pax2 , a paired - box transcription factor , has been identified as the responsible gene whose mutation is associated with the subgroup of cakut seen in the renal - coloboma syndrome .
pax2 is required for the growth and elongation of nefric duct ( nd ) prior to ureteral budding .
bor 's patients presents abnormalities of all parts of the ear associated with conductive , sensorineural , or mixed hearing impairment , branchial fistulae and cysts , and different cakut manifestations [ 27 , 28 ] .
bor is linked to haploinsufficiency for eya1 , a homolog of drosophila melanogaster gene eyes absent ( eya ) [ 28 - 30 ] . molecular genning testing for eya1 detects mutations in approximately 40% of individuals with the clinical diagnosis of bor .
the genetic cause for the most common forms of non - syndromic cakut are unknown . in non - syndromic
form of cakut the structural anomalies are confined only to the kidney and urinary tract .
the causes for the non - syndromic cakut types are considered multifactorial , resulting from the combination of epigenetic and environmental factors that affect genetically susceptible individuals [ 1 , 3 ] . only few genes [
32 , 33 ] has been implicated as responsible for nonsyndromic causes of human cakut ( table 1 ) .
renal abnormalities are also observed in close relatives of up to 10% of cakut patients , although these are frequently asymptomatic .
there are related cases of familial ureterocele , renal agenesis , hypodysplasia , renal tubular dysgenesis , multicystic dysplastic kidney ( mcdk ) , or vur [ 34 - 38 ] .
the phenotype often does not follow the classic mendelian inheritance : family members with the same genetic defect may have variable phenotypes , ranging from severe renal insufficiency to asymptomatic anomalies .
the occurrence of several presentations cakut in the same family indicates the possibility that a specific genetic mutation can lead to abnormalities in the development of urinary tract , however the final renal phenotype depends on both genetic background and environmental factors [ 1 , 3 ] .
it is a cystic out - pouching of the distal ureter into the urinary bladder [ 34 , 39 ] ( figs . 1 - 3 ) .
ureteroceles can be a diagnostic and therapeutic challenge with clinical symptoms arising from an abnormal spectrum embryogenesis mainly associated with the abnormal development of the ureteral intravesical
. they may be asymptomatic or appear with a wide range of clinical signs and symptoms , from recurrent urinary tract infection to bladder outlet obstruction and renal failure .
ureterocele usually causes obstruction of the affected renal unit and can be associated with varying degrees of dilatation of the renal pelvis and ureter , with or without the loss of kidney function .
ureteroceles can be categorized based on their relationship with the renal unit or on the distal ureteral configuration and location ( table 2 ) .
several forms of ureterocele classification have been proposed throughout the years , and the most popular one was established by the american academy of pediatrics in 1984 [ 34 , 40 ] .
the orthotopic or intravesical ureterocele is entirely located inside the bladder , whereas the ectopic has a portion permanently situated in the vesical neck or in the urethra .
double - system ureterocele is associated with the upper pole of a kidney with complete collecting system duplicity , whereas single - system ureterocele is associated with a kidney with one single ureter .
this classification of ureteroceles is useful in determining the type of treatment proposed and defining prognosis , especially with respect to the likelihood of the presence of bladder neck obstruction or occurrence of vesicoureteral reflux after treatment transurethral puncture [ 39 , 40 ] .
ureteroceles occur in approximately 1 in every 4000 children and are most common in whites .
ureteroceles are more frequent in female patients ( 4 - 6 times more common ) . in the adult population
the laterality shows a slight predominance on the left side , with near 10% bilateral disease .
orthotopic ureteroceles occur in 17 - 35% of cases , with an incidence of ectopic ureteroceles of approximately 80% in most pediatric series .
80% of ureteroceles are associated with the upper pole moiety of a duplex system . in these cases
single - system ectopic ureteroceles are uncommon and most often found in males [ 34 , 39 ] .  
series of family cases of ureterocele are described [ 34 , 41 - 44 ] in both single and double systems , suggesting the possibility of genetic predisposition . the first description of family cases of ureterocele was made in 1939 : simple system ureterocele in 29 years old identical twins . in 1980
a year earlier a family series was reported : dizygotic brothers affected by ureterocele , their parents are first cousins and the father and a sister had double collecting system . by 2005
there is a small number of specific studies on its genetic causes , most part of which groups this anomaly with other cakut .
it is probable that most cakut are examples of complex hereditary traits resulting from smaller mutations of multiple specific genes that are involved in the normal development of the urinary tract .  
two fundamental steps in ureter and bladder embryogenesis can be related to the ureterocele development , described by   as  pipe installation 
( development of the nephric duct ( nd ) or wolfian duct and of the ureteric bud ) and  plumbing 
this work aims to review the morphological and molecular stages of , as well as genetic abnormalities possibly related to ureterocele development .
the upper urinary tract ( kidneys and ureters ) has an ontological origin completely different from that of the lower tract ( bladder and urethra ) , and the perfect coupling of the two units is fundamental to allow a functional urinary flow .
the ureter originates as a nd epithelial protrusion that extends throughout the intermediate mesoderm at the level of the forelimb until the cloacal plate [ 48 , 49 ] .
the proximal portion of the bud invades the metanephric blastema , starts a successive elongation and bifurcation process , generating the renal collecting system .
the branch , in turn , ( bud portion located outside the metanephrine ) merely elongates until reaching the urethral plate . the metanephric mesenchyme of the upper portion of the ureter forms the nephrons and the renal stroma .
the distal mesenchyme has a smooth muscle with layers of longitudinal and cross - sectional orientation , forming the ureteral wall .  
the ectopy of the ureteric bud is considered the first false step that leads to several urogenital anomalies .
the formation process of the bud is not guided by the intrinsic position of the nd , but rather by signalers of the adjacent mesenchyme [ 47 , 51 ] .
the formation of a unique and properly located ureteric bud critically depends on the correct expression of the gndf ( glial - derived neurotrophic factor ) , which is produced by the metanephric tissue and couples with the c - ret tyrosine kinase receptor ( ret / gfr1 ) , with subsequent activation of several intracellular pathways leading to cellular shape changes , proliferation , migration and adherence to the epithelium of the adjacent nd , inducing the formation of the ureteric bud [ 47 , 48 , 52 ] . in humans ,
ret gene mutations are associated with the hirschsprung disease , neoplasia , and urinary tract anomalies ; similar alterations are found in mice .   the total or partial loss of the gndf signaling network results in emergence and growth failure of the ureteric bud , leading to renal agenesis or severe hypoplasia [ 49 , 53 ] .
hyperexpression leads to the formation of two or more ureteric buds , whereas anomalous spatial expression causes formation to occur earlier or later than usual , which is translated in the ectopic implantation of the ureter in the bladder or urethra [ 46 , 48 , 49 ] .
this is in agreement with the " bud theory " observed through extensive inspections of embryos and neonates .
this theory observes morphological correlations between the location of the ureteral orifice , renal dysplasia degree and ureter abnormalities .
a ureter rostral bud would be inserted last and in a low position in the bladder neck , in the urethra or in the sexual ducts , presenting an obstructive pattern , and may or may not be associated with ureterocele . a caudal ureteric bud would be inserted in the upper position , with early incorporation in the cloacal plate , a more lateral and cranial migration , less trigonal support and a short mesenchyme tunnel , being associated with vesical reflux .
the clinical observation of the weigert - meyer law supports this theory ; the duplex upper pole stands in a lower position , a generally obstructive pattern , whereas the lower pole opens in the upper side and is associated with vesicoureteral reflux [ 34 , 46 ] .
the osr1 gene regulates the activation of transcriptional factors such as eya1 , pax2 , sall1 .
proteins like slit2 and its robo2 receptor , and transcription factors like foxc1 and foxc2 are responsible for the repression of the gndf action in the rostral mesenchyme adjacent to the nd .
ablation of signaling system codifier genes of foxc1 and foxc2 transcription factors by slit 2 protein and its homologous receptor robo2 in the mesenchyme adjacent to the nd results in the spatial expansion of the metanephric blastema and of the activity area of gndf signals , with formation of multiple ureteric buds and ectopic ureters .
foxc1 homozygotes have an accessory ectopic bud , witch emerges more cranially from nd , usually enlarged and with ectopic distal connections .
a combined mutation of -catenin and gata3 leads to ret expression loss in mice embryos , but the -catenin expression is not affected by lack of gata3 , suggesting a supra - regulation process with a -catenin  gata3ret cascade in the nd .
in addition , the maintenance of the ret expression after the formation of the ureteric bud seems to be dependent of additional transcription factors as lim1 and emx2 and signaling through retinoic acid . in mice
, gata3 gene inactivation leads to defects in the proliferation of renal ducts , besides leading to premature differentiation of renal duct cells . in humans ,
gata3 gene functional loss is associated with the barakat syndrome , characterized by hypoparathyroidism , deafness , renal dysplasia / agenesis and vesicoureteral reflux .  
angiotensin type 2 receptor gene ( agtr2 ) prevent aberrant ureter budding from the nd .
rodents inactivated by genetic engineering for agtr2 had an initial rate of 2 - 3% of cakut , the penetrance was increased to almost 20% afters sequential cross breeding , indicating that this anomaly is also regulated by another gene ( s ) .
agtr2 null mutants care ectopic budding and many carry a duplex system . circa half of the mutants embryos showed abnormal initial budding either as two distinct buds or as one larger and broader bud relative to normal . the bmp4 gene ( bone morphogenic protein 4 ) , through the bmp4 activation molecule , serves as an inhibition factor to the gndf - ret signaler bud inductor , probably determining a new bud formation site [ 3 , 55 ] .
bmp4 serves as an inhibitory factor for the bud - inducing gdnf - ret signaling along the nd and the stalk of ureter , thereby determining the site of new bud formation .
the inhibiting effect of the bmp4 in the ureteric bud is inhibited by the secretion of the gremlin protein in the ureteric bud , allowing the localized expression of the gndf / ret network and the growth of the ureteric bud .
) generate ectopic or accessory ureteric bud , leading to different types of cakut , whereas homozygosis ( bmp4 -/- ) is always lethal [ 3 , 53 ] .
moreover , the bmp4 also acts as a signaler in smooth muscle and , possibly , in urothelium differentiation , in addition to acting in the mesenchyme of the lower urinary tract , activating regional transcriptional systems .
absorption and modulation failures of the mesenchymal tissue of the distal ureter and bladder could justify the occurrence of weakness in the vesical wall and subsequent dilation with ureterocele formation .
the diverse and prolonged activity of the bmp4 gene in the urinary tract morphogenesis could justify the multiple and different phenotypes observed in humans with bmp4 gene mutation .
this process consists of the mobilization of the distal portion of the ureteric bud until its ending position at the vesical wall .
the distal part of the ureter has to be translocated from the nd to the developing bladder wall [ 8 , 11 , 47 ] . after the initial contact of the mesonephric duct with the cloacal plate , the structures fuse .
recent studies show that there is no incorporation of the distal part in the primordial bladder tissue , but a nd apoptosis process that promotes direct contact between the epithelium of the ureteric bud and the epithelium of the cloacal plate . at this stage ,
the ureter suffers an 180-degrees rotation around the nd axis , forming a new connection point from the ureter to the bladder , causing the loss of contact with the nd and consequent spatial incorporation inside the bladder ( formation of the submucous tunnel and vesical trigone ) .
the apoptosis and remodeling mechanism of the nd and ureteric bud requires the expression of the lar - family - receptor ( leukocyte common antigen - related family receptor protein tyrosine phosphatases ) through the lar - rps , rptp and lar enzymes and their ptrf and s receptors , [ 11 , 46 ] which act in the down - regulation process of the ret chain .
the perfect balance of the lar - rtpp proapoptotic action and of the ret prosurvival action determines the correct position of the ureter in the bladder .
retinoic acid and receptors for ptprf and ptprs tyrosine kinase act in ret activity control at the transcriptional and proteinic levels , respectively .  
retinoic acid ( vitamin a active form ) , a key substance in the embryo morphogenesis , activates transcription pathways .
mutations in the aldh1a2 ( also called aldh1a2 ) , main synthesis enzyme of the retinoic acid , retinoic acid signaling loss and/or vitamin a deficiency are associated with hydronephrosis , megaureter and ureteral ectopy .
the complete elimination of the acid retinoic activity , whether by elimination of the rara / rarb or aldh1a2 receptor genes in the mesenchyme surrounding the mesonephric duct , results in the absence of distal ureter apoptosis , in addition to down - regulation in ret expression in the nd .
the retinoic acid action in the developing bladder is triggered by the up - regulation of cellular retinoic acid binding protein , retinoic acid early transcription 1 and retinoic acid receptor-. there is also the up - regulation of genes associated with cellular maturation , as mdk ( heparin binding growth factor ) , also induced by retinoic acid action .
mdk acts in angiogenesis , cellular differentiation , mesenchyme - epithelium interaction , and nervous system maturation .  
mutant mice for rara , rarb2 and aldh1a2 genes , and animals with inactivation of receptors for ptprf and ptprs tyrosine kinase present retinoic acid synthesis failures , with flaws in the apoptosis process of the nd , distal ectopic connection of the ureter to the vesical neck or urethra , and obstruction of the urine normal flow in the affected kidney . in ptprf;ptprs double mutants
, there is a decrease of more than 80% in apoptosis rates , which leads to delayed ureteral maturation , and the resulting obstruction commonly leads to ureterocele formation [ 5 , 20 , 25 ] . in mice with aldh1a2 deficiency , hydronephrosis and hydroureter not associated with ureterocele formation usually occur .
the deletion of aldh1a2 from the mesenchyme leads to a signaling reduction of rara , rarb and raldg2 receptors , with a decrease in ret expression in the nd .
the complete ablation of the aldh1a2 activity is enough to eliminate completely the apoptosis process of the nd [ 11 , 59 ] . in short ,
the migration and insertion of the nd and ureteric bud depend on ret activity and ret expression , and is mediated by the action of the retinoic acid and gata3 .
this communication pathway is crucial for the maturation of the distal ureter of the bladder .
it is a cystic out - pouching of the distal ureter into the urinary bladder [ 34 , 39 ] ( figs . 1 - 3 ) .
ureteroceles can be a diagnostic and therapeutic challenge with clinical symptoms arising from an abnormal spectrum embryogenesis mainly associated with the abnormal development of the ureteral intravesical .
they may be asymptomatic or appear with a wide range of clinical signs and symptoms , from recurrent urinary tract infection to bladder outlet obstruction and renal failure .
ureterocele usually causes obstruction of the affected renal unit and can be associated with varying degrees of dilatation of the renal pelvis and ureter , with or without the loss of kidney function .
ureteroceles can be categorized based on their relationship with the renal unit or on the distal ureteral configuration and location ( table 2 ) .
several forms of ureterocele classification have been proposed throughout the years , and the most popular one was established by the american academy of pediatrics in 1984 [ 34 , 40 ] .
the orthotopic or intravesical ureterocele is entirely located inside the bladder , whereas the ectopic has a portion permanently situated in the vesical neck or in the urethra .
double - system ureterocele is associated with the upper pole of a kidney with complete collecting system duplicity , whereas single - system ureterocele is associated with a kidney with one single ureter .
this classification of ureteroceles is useful in determining the type of treatment proposed and defining prognosis , especially with respect to the likelihood of the presence of bladder neck obstruction or occurrence of vesicoureteral reflux after treatment transurethral puncture [ 39 , 40 ] .
ureteroceles occur in approximately 1 in every 4000 children and are most common in whites .
ureteroceles are more frequent in female patients ( 4 - 6 times more common ) . in the adult population ,
the laterality shows a slight predominance on the left side , with near 10% bilateral disease .
orthotopic ureteroceles occur in 17 - 35% of cases , with an incidence of ectopic ureteroceles of approximately 80% in most pediatric series .
80% of ureteroceles are associated with the upper pole moiety of a duplex system . in these cases
single - system ectopic ureteroceles are uncommon and most often found in males [ 34 , 39 ] .  
series of family cases of ureterocele are described [ 34 , 41 - 44 ] in both single and double systems , suggesting the possibility of genetic predisposition . the first description of family cases of ureterocele was made in 1939 : simple system ureterocele in 29 years old identical twins . in 1980
a year earlier a family series was reported : dizygotic brothers affected by ureterocele , their parents are first cousins and the father and a sister had double collecting system . by 2005
there is a small number of specific studies on its genetic causes , most part of which groups this anomaly with other cakut .
it is probable that most cakut are examples of complex hereditary traits resulting from smaller mutations of multiple specific genes that are involved in the normal development of the urinary tract .  
two fundamental steps in ureter and bladder embryogenesis can be related to the ureterocele development , described by   as  pipe installation  ( development of the nephric duct ( nd ) or wolfian duct and of the ureteric bud ) and  plumbing 
this work aims to review the morphological and molecular stages of , as well as genetic abnormalities possibly related to ureterocele development .
the upper urinary tract ( kidneys and ureters ) has an ontological origin completely different from that of the lower tract ( bladder and urethra ) , and the perfect coupling of the two units is fundamental to allow a functional urinary flow .
the ureter originates as a nd epithelial protrusion that extends throughout the intermediate mesoderm at the level of the forelimb until the cloacal plate [ 48 , 49 ] .
the proximal portion of the bud invades the metanephric blastema , starts a successive elongation and bifurcation process , generating the renal collecting system .
the branch , in turn , ( bud portion located outside the metanephrine ) merely elongates until reaching the urethral plate . the metanephric mesenchyme of the upper portion of the ureter forms the nephrons and the renal stroma .
the distal mesenchyme has a smooth muscle with layers of longitudinal and cross - sectional orientation , forming the ureteral wall .  
the ectopy of the ureteric bud is considered the first false step that leads to several urogenital anomalies .
the formation process of the bud is not guided by the intrinsic position of the nd , but rather by signalers of the adjacent mesenchyme [ 47 , 51 ] .
the formation of a unique and properly located ureteric bud critically depends on the correct expression of the gndf ( glial - derived neurotrophic factor ) , which is produced by the metanephric tissue and couples with the c - ret tyrosine kinase receptor ( ret / gfr1 ) , with subsequent activation of several intracellular pathways leading to cellular shape changes , proliferation , migration and adherence to the epithelium of the adjacent nd , inducing the formation of the ureteric bud [ 47 , 48 , 52 ] . in humans ,
ret gene mutations are associated with the hirschsprung disease , neoplasia , and urinary tract anomalies ; similar alterations are found in mice .   the total or partial loss of the gndf signaling network results in emergence and growth failure of the ureteric bud , leading to renal agenesis or severe hypoplasia [ 49 , 53 ] .
hyperexpression leads to the formation of two or more ureteric buds , whereas anomalous spatial expression causes formation to occur earlier or later than usual , which is translated in the ectopic implantation of the ureter in the bladder or urethra [ 46 , 48 , 49 ] .
this is in agreement with the " bud theory " observed through extensive inspections of embryos and neonates
. this theory observes morphological correlations between the location of the ureteral orifice , renal dysplasia degree and ureter abnormalities .
a ureter rostral bud would be inserted last and in a low position in the bladder neck , in the urethra or in the sexual ducts , presenting an obstructive pattern , and may or may not be associated with ureterocele . a caudal ureteric bud would be inserted in the upper position , with early incorporation in the cloacal plate , a more lateral and cranial migration , less trigonal support and a short mesenchyme tunnel , being associated with vesical reflux .
the clinical observation of the weigert - meyer law supports this theory ; the duplex upper pole stands in a lower position , a generally obstructive pattern , whereas the lower pole opens in the upper side and is associated with vesicoureteral reflux [ 34 , 46 ] .
the osr1 gene regulates the activation of transcriptional factors such as eya1 , pax2 , sall1 .
proteins like slit2 and its robo2 receptor , and transcription factors like foxc1 and foxc2 are responsible for the repression of the gndf action in the rostral mesenchyme adjacent to the nd .
ablation of signaling system codifier genes of foxc1 and foxc2 transcription factors by slit 2 protein and its homologous receptor robo2 in the mesenchyme adjacent to the nd results in the spatial expansion of the metanephric blastema and of the activity area of gndf signals , with formation of multiple ureteric buds and ectopic ureters .
foxc1 homozygotes have an accessory ectopic bud , witch emerges more cranially from nd , usually enlarged and with ectopic distal connections .
. a combined mutation of -catenin and gata3 leads to ret expression loss in mice embryos , but the -catenin expression is not affected by lack of gata3 , suggesting a supra - regulation process with a -catenin  gata3ret cascade in the nd .
in addition , the maintenance of the ret expression after the formation of the ureteric bud seems to be dependent of additional transcription factors as lim1 and emx2 and signaling through retinoic acid . in mice
, gata3 gene inactivation leads to defects in the proliferation of renal ducts , besides leading to premature differentiation of renal duct cells . in humans ,
gata3 gene functional loss is associated with the barakat syndrome , characterized by hypoparathyroidism , deafness , renal dysplasia / agenesis and vesicoureteral reflux .  
angiotensin type 2 receptor gene ( agtr2 ) prevent aberrant ureter budding from the nd .
rodents inactivated by genetic engineering for agtr2 had an initial rate of 2 - 3% of cakut , the penetrance was increased to almost 20% afters sequential cross breeding , indicating that this anomaly is also regulated by another gene ( s ) .
agtr2 null mutants care ectopic budding and many carry a duplex system . circa half of the mutants embryos showed abnormal initial budding either as two distinct buds or as one larger and broader bud relative to normal . the bmp4 gene ( bone morphogenic protein 4 ) , through the bmp4 activation molecule , serves as an inhibition factor to the gndf - ret signaler bud inductor , probably determining a new bud formation site [ 3 , 55 ] .
bmp4 serves as an inhibitory factor for the bud - inducing gdnf - ret signaling along the nd and the stalk of ureter , thereby determining the site of new bud formation .
the inhibiting effect of the bmp4 in the ureteric bud is inhibited by the secretion of the gremlin protein in the ureteric bud , allowing the localized expression of the gndf / ret network and the growth of the ureteric bud .
) generate ectopic or accessory ureteric bud , leading to different types of cakut , whereas homozygosis ( bmp4 -/- ) is always lethal [ 3 , 53 ] .
moreover , the bmp4 also acts as a signaler in smooth muscle and , possibly , in urothelium differentiation , in addition to acting in the mesenchyme of the lower urinary tract , activating regional transcriptional systems .
absorption and modulation failures of the mesenchymal tissue of the distal ureter and bladder could justify the occurrence of weakness in the vesical wall and subsequent dilation with ureterocele formation .
the diverse and prolonged activity of the bmp4 gene in the urinary tract morphogenesis could justify the multiple and different phenotypes observed in humans with bmp4 gene mutation .
this process consists of the mobilization of the distal portion of the ureteric bud until its ending position at the vesical wall .
the distal part of the ureter has to be translocated from the nd to the developing bladder wall [ 8 , 11 , 47 ] . after the initial contact of the mesonephric duct with the cloacal plate , the structures fuse .
recent studies show that there is no incorporation of the distal part in the primordial bladder tissue , but a nd apoptosis process that promotes direct contact between the epithelium of the ureteric bud and the epithelium of the cloacal plate . at this stage ,
the ureter suffers an 180-degrees rotation around the nd axis , forming a new connection point from the ureter to the bladder , causing the loss of contact with the nd and consequent spatial incorporation inside the bladder ( formation of the submucous tunnel and vesical trigone ) .
the apoptosis and remodeling mechanism of the nd and ureteric bud requires the expression of the lar - family - receptor ( leukocyte common antigen - related family receptor protein tyrosine phosphatases ) through the lar - rps , rptp and lar enzymes and their ptrf and s receptors , [ 11 , 46 ] which act in the down - regulation process of the ret chain .
the perfect balance of the lar - rtpp proapoptotic action and of the ret prosurvival action determines the correct position of the ureter in the bladder .
retinoic acid and receptors for ptprf and ptprs tyrosine kinase act in ret activity control at the transcriptional and proteinic levels , respectively .  
retinoic acid ( vitamin a active form ) , a key substance in the embryo morphogenesis , activates transcription pathways .
mutations in the aldh1a2 ( also called aldh1a2 ) , main synthesis enzyme of the retinoic acid , retinoic acid signaling loss and/or vitamin a deficiency are associated with hydronephrosis , megaureter and ureteral ectopy . the complete elimination of the acid retinoic activity , whether by elimination of the rara / rarb or aldh1a2 receptor genes in the mesenchyme surrounding the mesonephric duct , results in the absence of distal ureter apoptosis , in addition to down - regulation in ret expression in the nd .
the retinoic acid action in the developing bladder is triggered by the up - regulation of cellular retinoic acid binding protein , retinoic acid early transcription 1 and retinoic acid receptor-. there is also the up - regulation of genes associated with cellular maturation , as mdk ( heparin binding growth factor ) , also induced by retinoic acid action .
mdk acts in angiogenesis , cellular differentiation , mesenchyme - epithelium interaction , and nervous system maturation .  
mutant mice for rara , rarb2 and aldh1a2 genes , and animals with inactivation of receptors for ptprf and ptprs tyrosine kinase present retinoic acid synthesis failures , with flaws in the apoptosis process of the nd , distal ectopic connection of the ureter to the vesical neck or urethra , and obstruction of the urine normal flow in the affected kidney . in ptprf;ptprs double mutants
, there is a decrease of more than 80% in apoptosis rates , which leads to delayed ureteral maturation , and the resulting obstruction commonly leads to ureterocele formation [ 5 , 20 , 25 ] . in mice with aldh1a2 deficiency , hydronephrosis and hydroureter
the deletion of aldh1a2 from the mesenchyme leads to a signaling reduction of rara , rarb and raldg2 receptors , with a decrease in ret expression in the nd .
the complete ablation of the aldh1a2 activity is enough to eliminate completely the apoptosis process of the nd [ 11 , 59 ] . in short ,
the migration and insertion of the nd and ureteric bud depend on ret activity and ret expression , and is mediated by the action of the retinoic acid and gata3 .
this communication pathway is crucial for the maturation of the distal ureter of the bladder .
urinary tract formation is a complex process , dependent of the interaction of multiple genes and their sub - product .
ureterocele is one of these anomalies , and its occurrence may be related to the initial formation process of the ureter , its migration and incorporation to the cloacal plate , being resulting from interaction of innumerous morphological , cellular and biochemical factors .
the collaboration of several multidisciplinary research centers worldwide is necessary to discover the molecular and genetic pathogenesis of cakut , improving care for patients and their families by performing personalized medical treatment based on detailed understanding of the molecular pathogenesis of the disease , early diagnosis strategies , monitoring and treatment .
 congenital anomalies of the kidney and urinary tract ( cakut ) form a group of heterogeneous disorders that affect the kidneys , ureters and bladder , with frequent asynchronous presentations and multiple cakut associations in the same individual . 
 urinary tract formation is a complex process , dependent of the interaction of multiple genes and their sub - product . 
 the same genic alterations can lead to different molecular expressions and different morphological anomalies . 
 the ureterocele is a cystic dilation of the distal intramural ureter , resulting in obstruction of urine flow , dilation of the ureter and renal pelvis and loss of renal function . 
 two key steps in the urinary tract ontogenesis may be related to ureterocele development : formation and migration of the ureteric bud and its incorporation in the bladder . 
 this review aims to describe the morphological , cellular and biochemical steps , as well as the genes involved in the occurrence of this anomaly . 
INTRODUCTION
Ureterocele
Mesonephric Duct and Ureteric Bud Formation
Maturation of the Distal Ureter and its Incorporation in the Bladder
CONCLUSION
CONFLICT OF INTEREST