Wnt11 and Ret/Gdnf pathways cooperate in regulating ureteric branching during metanephric kidney development
Wnt11 and Ret/Gdnf pathways cooperate in regulating ureteric branching during metanephric kidney development
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DOI：
10.1242/dev.00520
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发表时间：
2003-07-01
期刊：
影响因子：
4.6
通讯作者：
McMahon, AP
中科院分区：
文献类型：
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作者：
Majumdar, A;Vainio, S;McMahon, AP
输尿管上皮和后肾间充质之间的相互细胞-细胞相互作用需要驱动胚胎肾的生长和分化完成。Wolffian管衍生的输尿管芽的分支形态发生在输尿管尖端的产生和集合管系统的发育中是不可或缺的。Wnt 11是分泌型糖蛋白Wnt超家族的成员，在脊椎动物胚胎发育过程中具有重要的调节功能，在分支输尿管上皮的尖端特异性表达。在这项工作中，我们探讨了Wnt 11在输尿管分支的作用，并使用Wnt 11位点的靶向突变作为切入点，调查收集管形态发生的遗传控制。Wnt 11基因突变导致新生小鼠输尿管分支形态发生缺陷和随后的肾脏发育不全。Wnt 11的功能，部分，通过维持正常的表达水平的基因编码胶质细胞源性神经营养因子（Gdnf）。GDNF编码间质产生的Ret酪氨酸激酶受体的配体，其对正常输尿管分支至关重要。相反，在没有Ret/Gdnf信号传导的情况下，Wnt 11表达减少。与Wnt 11和Ret/Gdnf之间的相互作用调节分支过程的想法一致，Wnt 11和Ret突变在输尿管分支形态发生中协同相互作用。基于这些观察结果，我们得出结论，Wnt 11和Ret/Gdnf合作，在一个积极的自动调节反馈回路，以协调输尿管分支，通过保持适当的平衡Wnt 11表达输尿管上皮和Gdnf表达间充质，以确保持续的后肾发育。
Reciprocal cell-cell interactions between the ureteric epithelium and the metanephric mesenchyme are needed to drive growth and differentiation of the embryonic kidney to completion. Branching morphogenesis of the Wolffian duct derived ureteric bud is integral in the generation of ureteric tips and the elaboration of the collecting duct system. Wnt11, a member of the Wnt superfamily of secreted glycoproteins, which have important regulatory functions during vertebrate embryonic development, is specifically expressed in the tips of the branching ureteric epithelium. In this work, we explore the role of Wnt11 in ureteric branching and use a targeted mutation of the Wnt11 locus as an entrance point into investigating the genetic control of collecting duct morphogenesis. Mutation of the Wnt11 gene results in ureteric branching morphogenesis defects and consequent kidney hypoplasia in newborn mice. Wnt11 functions, in part, by maintaining normal expression levels of the gene encoding glial cell-derived neurotrophic factor (Gdnf). Gdnf encodes a mesenchymally produced ligand for the Ret tyrosine kinase receptor that is crucial for normal ureteric branching. Conversely, Wnt11 expression is reduced in the absence of Ret/Gdnf signaling. Consistent with the idea that reciprocal interaction between Wnt11 and Ret/Gdnf regulates the branching process, Wnt11 and Ret mutations synergistically interact in ureteric branching morphogenesis. Based on these observations, we conclude that Wnt11 and Ret/Gdnf cooperate in a positive autoregulatory feedback loop to coordinate ureteric branching by maintaining an appropriate balance of Wnt11-expressing ureteric epithelium and Gdnf-expressing mesenchyme to ensure continued metanephric development.