Critical and distinct roles for key RET tyrosine docking sites in renal development.
Molecular mechanisms that lead to congenital anomalies of kidneys and the lower urinary tract (CAKUT) are poorly understood. To elucidate the molecular basis for signaling specificity of GDNF-mediated RET signaling in kidney development, we characterized mice that exclusively express either the human RET9 or RET51 isoform, or express these isoforms with individual mutations in docking tyrosines for PTB and SH2-domain-containing adaptors Src (Y981), PLCgamma (Y1015), and Shc (Y1062). Our results provide evidence for differential and isoform-specific roles of these docking sites in murine kidney development. Homozygous Ret(RET9) and Ret(RET51) mice were viable and show normally developed kidneys, indicating redundant roles of human RET isoforms in murine kidney development. In the context of the RET51 isoform, only mutation of the docking Tyr 1015 (Y1015F) resulted in severe renal anomalies. These included bilateral megaureters and multicystic kidneys that were caused by supernumerary ureteric buds that fail to separate from the wolffian duct as well as decreased branching morphogenesis. Similar kidney and ureter defects were observed in RET9(Y1015F) mice that contain the Y1015F mutation in the RET9 isoform. Interestingly, loss of RET9(Y1062)-mediated AKT/MAPK activation resulted in renal agenesis or kidney rudiments, whereas mutation of this residue in RET51 had no obvious effect on AKT/MAPK activity and renal development. These results reveal novel roles of key RET-dependent signaling pathways in embryonic kidney development and provide murine models and new insights into the molecular basis for CAKUT.
Jain
Sanjay
S
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA. jainsa@msnotes.wustl.edu
Encinas
Mario
M
Johnson
Eugene M
EM
Milbrandt
Jeffrey
J
D000818:Animals; D017209:Apoptosis; D006066:Gonads / Q000502:physiology; D006801:Humans; D007668:Kidney / Q000002:abnormalities / Q000196:embryology* / Q000254:growth & development; D051379:Mice; D008817:Mice, Mutant Strains; D009024:Morphogenesis / Q000235:genetics / Q000502:physiology; D009154:Mutation; D010649:Phenylalanine / Q000235:genetics / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism*; D014513:Ureter / Q000502:physiology
D020033:Protein Isoforms; D014443:Tyrosine; D010649:Phenylalanine; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; C494999:Ret protein, mouse; D051966:Phospholipase C gamma