Critical and distinct roles for key RET tyrosine docking sites in renal development
Critical and distinct roles for key RET tyrosine docking sites in renal development
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DOI：
10.1101/gad.1387206
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发表时间：
2006-02-01
影响因子：
10.5
通讯作者：
Milbrandt, J
中科院分区：
文献类型：
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作者：
Jain, S;Encinas, M;Milbrandt, J
导致先天性肾脏和下尿路异常（CAKUT）的分子机制知之甚少。为了阐明GDNF介导的RET信号在肾脏发育中的信号特异性的分子基础，我们表征了只表达人RET 9或RET 51同种型，或表达这些同种型的小鼠，这些同种型在PTB和含SH 2结构域的衔接子Src（Y 981）、PLC γ（Y1015）和Shc（Y1062）的对接酪氨酸中具有个体突变。我们的研究结果提供了证据的差异和亚型特异性的作用，这些对接站点在小鼠肾脏发育。纯合子Ret（RET 9）和Ret（RET 51）小鼠存活，并显示正常发育的肾脏，表明人RET同种型在鼠肾脏发育中的冗余作用。在RET 51亚型的背景下，只有对接Tyr 1015（Y1015 F）的突变导致严重的肾脏异常。这些包括双侧巨输尿管和多囊肾，这是由于多余的输尿管芽未能与输尿管导管分离以及分支形态发生减少造成的。在RET 9同种型中含有Y1015 F突变的RET 9（Y1015 F）小鼠中观察到类似的肾脏和输尿管缺陷。有趣的是，RET 9（Y1062）介导的AKT/MAPK活性的丧失导致肾发育不全或肾雏形，而RET 51中该残基的突变对AKT/MAPK活性和肾发育没有明显影响。这些结果揭示了关键RET依赖性信号通路在胚胎肾脏发育中的新作用，并为CAKUT的分子基础提供了小鼠模型和新的见解。
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), PLC gamma (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.