Gene discovery and vesicoureteric reflux

Murawski, Inga J.; Gupta, Indra R.

doi:10.1007/s00467-007-0704-y

Cited by 29 publications

(38 citation statements)

References 56 publications

(75 reference statements)

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“…The majority of the lower urinary tract anomalies identified to date originate from defects in the induction, growth or differentiation of the kidneys and ureters (Mackie and Stephens, 1975;Murawski and Gupta, 2008;Tanagho, 1976). ND insertion occurs prior to the onset of kidney development; hence, little attention has been paid to developmental defects at this early stage.…”

Section: Failure Of Nephric Duct/cloaca Fusion: a Novel Cause Of Lowementioning

confidence: 99%

“…Recent evidence supports this model and further shows that ureter maturation depends on apoptotic elimination of the common nephric duct (CND), the most caudal segment of the ND (Batourina et al, 2005;). This process brings the ureter into contact with the bladder epithelium, where the caudal ureter undergoes apoptosis forming a new ureteral orifice in the bladder primordium (Batourina et al, 2002;Batourina et al, 2005;Mendelsohn, 2009;Murawski and Gupta, 2008;. Subsequent growth of the bladder moves the ureteral orifice to its final position in the bladder.…”

Section: Introductionmentioning

confidence: 99%

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Nephric duct insertion is a crucial step in urinary tract maturation that is regulated by aGata3-Raldh2-Retmolecular network in mice

et al. 2011

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SUMMARYUrinary tract development depends on a complex series of events in which the ureter moves from its initial branch point on the nephric duct (ND) to its final insertion site in the cloaca (the primitive bladder and urethra). Defects in this maturation process can result in malpositioned ureters and hydronephrosis, a common cause of renal disease in children. Here, we report that insertion of the ND into the cloaca is an unrecognized but crucial step that is required for proper positioning of the ureter and that depends on Ret signaling. Analysis of Ret mutant mice at birth reveals hydronephrosis and defective ureter maturation, abnormalities that our results suggest are caused, at least in part, by delayed insertion of the ND. We find a similar set of malformations in mutants lacking either Gata3 or Raldh2. We show that these factors act in parallel to regulate ND insertion via Ret. Morphological analysis of ND extension in wild-type embryos reveals elaborate cellular protrusions at ND tips that are not detected in Ret, Gata3 or Raldh2 mutant embryos, suggesting that these protrusions may normally be important for fusion with the cloaca. Together, our studies reveal a novel Ret-dependent event, ND insertion, that, when abnormal, can cause obstruction and hydronephrosis at birth; whether ND defects underlie similar types of urinary tract abnormalities in humans is an interesting possibility.

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Section: Failure Of Nephric Duct/cloaca Fusion: a Novel Cause Of Lowementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nephric duct insertion is a crucial step in urinary tract maturation that is regulated by aGata3-Raldh2-Retmolecular network in mice

et al. 2011

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“…In the urinary system, complete loss or misexpression of Ret results in bilateral renal agenesis, dysplasia, defective insertion of the WD into cloaca and defective ureter maturation (Batourina et al, 2002;Chia et al, 2011;Jain et al, 2006b;Jain et al, 2010;Murawski and Gupta, 2008;Schuchardt et al, 1994;Shakya et al, 2005;Uetani et al, 2009). RET signaling in kidneys is activated by the formation of a receptor complex with glial cell line-derived neurotrophic factor (GDNF) and GFR1 co-receptor (Jain, 2009).…”

Section: Introductionmentioning

confidence: 99%

Novel mechanisms of early upper and lower urinary tract patterning regulated by RetY1015 docking tyrosine in mice

et al. 2012

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SUMMARYMutations in the receptor tyrosine kinase RET are associated with congenital anomalies of kidneys or urinary tract (CAKUT). RET tyrosine Y1015 is the docking site for PLC, a major regulator of RET signaling. Abrogating signaling via Y1015 causes CAKUT that are markedly different than renal agenesis in Ret-null or RetY1062F mutant mice. We performed analysis of Y1015F mutant upper and lower urinary tracts in mice to delineate its molecular and developmental roles during early urinary tract formation. We found that the degeneration of the common nephric ducts (CND), the caudal-most Wolffian duct (WD) segment, depends on Y1015 signals. The CNDs in Y1015F mutants persist owing to increased proliferation and reduced apoptosis, and showed abundance of phospho-ERK-positive cells. In the upper urinary tract, the Y1015 signals are required for proper patterning of the mesonephros and metanephros. Timely regression of mesonephric mesenchyme and proper demarcation of mesonephric and metanephric mesenchyme from the WD depends on RetY1015 signaling. We show that the mechanism of de novo ectopic budding is via increased ERK activity due to abnormal mesenchymal GDNF expression. Although reduction in GDNF dosage improved CAKUT it did not affect delayed mesenchyme regression. Experiments using whole-mount immunofluorescence confocal microscopy and explants cultures of early embryos with ERK-specific inhibitors suggest an imbalance between increased proliferation, decreased apoptosis and increased ERK activity as a mechanism for WD defects in RetY1015F mice. Our work demonstrates novel inhibitory roles of RetY1015 and provides a possible mechanistic explanation for some of the confounding broad range phenotypes in individuals with CAKUT.

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“…48 Furthermore, abnormalities during embryogenesis, especially a caudally shifted ureteric bud, predispose to ureteric reflux in animal models. 40,[49][50][51] the precise position at which the ureteric bud grows out from the mesonephric duct is critical. a range of abnormalities of the kidneys and urinary tract can result from aberrant or multiple budding.…”

Section: Vur Is a Complex Diseasementioning

confidence: 99%

Genetics of vesicoureteral reflux

et al. 2011

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| Primary vesicoureteral reflux (VUR) is the most common urological anomaly in children, affecting 1-2% of the pediatric population and 30-40% of children presenting with urinary tract infections (UTIs). Refluxassociated nephropathy is a major cause of childhood hypertension and chronic renal failure. The hereditary and familial nature of VUR is well recognized and several studies have reported that siblings of children with VUR have a higher incidence of reflux than the general pediatric population. Familial clustering of VUR implies that genetic factors have an important role in its pathogenesis, but no single major locus or gene for VUR has yet been identified and most researchers now acknowledge that VUR is genetically heterogeneous. Improvements in genome-scan techniques and continuously increasing knowledge of the genetic basis of VUR should help us to further understand its pathogenesis.

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Gene discovery and vesicoureteric reflux

Cited by 29 publications

References 56 publications

Nephric duct insertion is a crucial step in urinary tract maturation that is regulated by aGata3-Raldh2-Retmolecular network in mice

Nephric duct insertion is a crucial step in urinary tract maturation that is regulated by aGata3-Raldh2-Retmolecular network in mice

Novel mechanisms of early upper and lower urinary tract patterning regulated by RetY1015 docking tyrosine in mice

Genetics of vesicoureteral reflux

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