Organotypic specificity of key RET adaptor-docking sites in the pathogenesis of neurocristopathies and renal malformations in mice

Jain, Sanjay; Knoten, Amanda; Hoshi, Masato; Wang, Hongtao; Vohra, Bhupinder P.S.; Heuckeroth, Robert O.; Milbrandt, Jeffrey

doi:10.1172/jci41619

Cited by 55 publications

(52 citation statements)

References 55 publications

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“…Loss of Ret leads to loss of caudal migration of the ND (Chia et al, 2011). Mutation of the different docking-site tyrosines on Ret can differentially activate subsets of downstream pathways (Jain et al, 2010). Ret Y1015 serves as the docking site for PLCγ, whereas RetY1062 is the docking site for activation of the Ras/MAPK and PI3K pathways in the urinary tract (Davis et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Yap and Taz are required for Ret-dependent urinary tract morphogenesis

et al. 2015

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Despite the high occurrence of congenital abnormalities of the lower urinary tract in humans, the molecular, cellular and morphological aspects of their development are still poorly understood. Here, we use a conditional knockout approach to inactivate within the nephric duct (ND) lineage the two effectors of the Hippo pathway, Yap and Taz. Deletion of Yap leads to hydronephrotic kidneys with blind-ending megaureters at birth. In Yap mutants, the ND successfully migrates towards, and contacts, the cloaca. However, close analysis reveals that the tip of the Yap −/− ND forms an aberrant connection with the cloaca and does not properly insert into the cloaca, leading to later detachment of the ND from the cloaca. Taz deletion from the ND does not cause any defect, but analysis of Yap −/− ;Taz −/− NDs indicates that both genes play partially redundant roles in ureterovesical junction formation. Aspects of the Yap −/− phenotype resemble hypersensitivity to RET signaling, including excess budding of the ND, increased phospho-ERK and increased expression of Crlf1, Sprouty1, Etv4 and Etv5. Importantly, the Yap ND−/− ND phenotype can be largely rescued by reducing Ret gene dosage. Taken together, these results suggest that disrupting Yap/Taz activities enhances Ret pathway activity and contributes to pathogenesis of lower urinary tract defects in human infants.

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Section: Discussionmentioning

confidence: 99%

Yap and Taz are required for Ret-dependent urinary tract morphogenesis

et al. 2015

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“…Routine histological assessment was carried out on Hematoxylin and Eosin-stained tissue sections. Immunostaining of whole organs and tissue sections was as previously described (Jain et al, 2006a;Jain et al, 2010). The antibodies used were: anti-Pax2 (Covance, 1:100), anti-GFP (Aves, 1:200), anti-mouse E-cadherin (R&D, 1:50) and anti-phospho ERK1/2 and Histone H3 (Cell Signaling, 1:100).…”

Section: Morphological and Immunofluorescence Analysismentioning

confidence: 99%

“…Whole-mount specimens were visualized with a fluorescence stereomicroscope and tissue sections on a compound upright microscope; images were captured as previously reported (Jain et al, 2010). Time-lapse microscopy was performed on a motorized inverted microscope (Nikon TE2000, Nikon Instruments, Melville, NY) and the images were captured by HQ2 (Photometrics, Tucson, AZ) camera.…”

Section: Microscopymentioning

confidence: 99%

“…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%

“…These regulate cellular processes such as proliferation, migration, differentiation, survival and self-renewal to ensure normal development. In our previous studies, we generated individual Ret-docking tyrosine mutant mice and discovered that RetY1015 (docking site for PLC) and RetY1062 (which activates the PI3K/MAPK pathway through adaptors such as Shc) have distinct roles in the UT and the autonomic nervous systems (Jain et al, 2006a;Jain et al, 2010). RetY1015F mutants display spectrum of CAKUT-like defects, including supernumerary ureters, mega-ureters and dysplasia, as well as abnormally positioned gonads and failure of gonadal ducts to separate from the ureter.…”

Section: Introductionmentioning

confidence: 99%

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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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Evidence for a recurrent microdeletion at chromosome 16p11.2 associated with congenital anomalies of the kidney and urinary tract (CAKUT) and Hirschsprung disease

Sampson

Coughlin

Kaplan

et al. 2010

American J of Med Genetics Pt A

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Congenital Anomalies of the Kidney and Urinary Tract can be associated with Hirschsprung disease. We report on three children with a similar 16p11.2 microdeletion with a spectrum of clinical anomalies consisting of congenital anomalies of the kidney and urinary tract in two patients (Patients 1 and 2) and Hirschsprung disease in two patients (Patients 1 and 3), leading us to hypothesize that a gene in this region is associated with these phenotypes. Patient 1 presented with left renal agenesis, grade-IV vesicoureteral reflux, and Hirschsprung disease, Patient 2 with left renal agenesis, chronic kidney disease, chronic constipation, seizures, and developmental delay, and Patient 3 with Hirschsprung disease and normal kidneys. Genome-wide microarray analysis demonstrated overlapping microdeletions within 16p11.2. The shortest region of overlap in the three patients contained only eight genes, including the SH2 domain-containing binding protein 1 (SH2B1), an adaptor protein which has been implicated in enhancement of the tyrosine kinase activity of RET, whose role in developmental disease of the kidney and enteric enervation is well established. Our findings suggest that 16p11.2 deletions are associated with abnormalities of renal and enteric development and we hypothesize that deletion of SH2B1 may account for the observed phenotype.

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Organotypic specificity of key RET adaptor-docking sites in the pathogenesis of neurocristopathies and renal malformations in mice

Cited by 55 publications

References 55 publications

Yap and Taz are required for Ret-dependent urinary tract morphogenesis

Yap and Taz are required for Ret-dependent urinary tract morphogenesis

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

Evidence for a recurrent microdeletion at chromosome 16p11.2 associated with congenital anomalies of the kidney and urinary tract (CAKUT) and Hirschsprung disease

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