Max Delbrueck Center for Molecular Medicine (MDC), Robert-Roessle-Strasse 10, 13125 Berlin, Germany.
Dev Biol. 2011 Dec 15;360(2):310-7. doi: 10.1016/j.ydbio.2011.09.029. Epub 2011 Oct 8.
The tyrosine phosphatase Shp2 acts downstream of various growth factors, hormones or cytokine receptors. Mutations of the Shp2 gene are associated with several human diseases. Here we have ablated Shp2 in the developing kidneys of mice, using the ureteric bud epithelium-specific Hoxb7/Cre. Mutant mice produced a phenotype that is similar to mutations of the genes of the GDNF/Ret receptor system, that is: strongly reduced ureteric bud branching and downregulation of the Ret target genes Etv4 and Etv5. Shp2 mutant embryonic kidneys also displayed reduced cell proliferation at the branch tips and branching defects, which could not be overcome by GDNF in organ culture. We also examined compound mutants of Shp2 and Sprouty1, which is an inhibitor of receptor tyrosine kinase signaling in the kidney. Sprouty1 single mutants produce supernumerary ureteric buds, which branch excessively. Sprouty1 mutants rescued branching deficits in Ret(-/-) and GDNF(-/-) kidneys. Sprouty1; Shp2 double mutants showed no rescue of kidney branching. Our data thus indicate an intricate interplay of Shp2 and Sprouty1 in signaling downstream of receptor tyrosine kinases during kidney development. Apparently, Shp2 mediates not only GDNF/Ret but also signaling by other receptor tyrosine kinases in branching morphogenesis of the embryonic kidney.
酪氨酸磷酸酶 Shp2 作为多种生长因子、激素或细胞因子受体的下游因子发挥作用。Shp2 基因突变与多种人类疾病相关。在这里，我们使用输尿管芽上皮特异性 Hoxb7/Cre 在发育中的肾脏中敲除了 Shp2。突变小鼠表现出类似于 GDNF/Ret 受体系统基因突变的表型，即：输尿管芽分支强烈减少，Ret 靶基因 Etv4 和 Etv5 的表达下调。Shp2 突变胚胎肾脏在分支尖端的细胞增殖也减少，并且分支缺陷不能在器官培养中通过 GDNF 克服。我们还检查了 Shp2 和 Sprouty1 的复合突变体，Sprouty1 是肾脏中受体酪氨酸激酶信号的抑制剂。Sprouty1 单突变体产生过多的输尿管芽，过度分支。Sprouty1 突变体挽救了 Ret(-/-)和 GDNF(-/-)肾脏中的分支缺陷。Sprouty1;Shp2 双突变体显示对肾脏分支的拯救作用。因此，我们的数据表明 Shp2 和 Sprouty1 在肾脏发育过程中受体酪氨酸激酶信号下游的信号转导中存在复杂的相互作用。显然，Shp2 不仅介导 GDNF/Ret，而且还介导其他受体酪氨酸激酶在胚胎肾脏分支形态发生中的信号转导。
