Gata3 acts downstream of beta-catenin signaling to prevent ectopic metanephric kidney induction.
Gata3 acts downstream of beta-catenin signaling to prevent ectopic metanephric kidney induction.
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DOI：
10.1371/journal.pgen.1000316
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发表时间：
2008-12
期刊：
影响因子：
4.5
通讯作者：
Bouchard M
中科院分区：
文献类型：
--
作者：
Grote D;Boualia SK;Souabni A;Merkel C;Chi X;Costantini F;Carroll T;Bouchard M
后肾诱导主要依赖于肾（或Wolffian）管尾侧区域间充质-上皮相互作用。在这一过程中，后肾间质分泌的GDNF通过激活肾管上皮中表达的Ret受体诱导输尿管出芽。这一途径的调节失败被认为是影响泌尿生殖系统的大部分发育异常的原因。在这里，我们发现转录因子基因Gata3的肾管特异性失活导致大量异位输尿管萌芽。这导致一系列泌尿生殖系统畸形，包括肾发育不全、双系统和输尿管积水，以及输精管增生和子宫发育不全。发育缺陷的可变性使人想起在人类中观察到的先天性肾和尿路异常（CAKUT）。我们发现Gata3失活导致肾管细胞过早分化和Ret受体基因表达缺失。这些变化最终影响肾管上皮稳态，导致仍表达Ret受体的分散细胞异位出芽。重要的是，这些异位芽的形成需要GDNF/Ret和Fgf信号活动。我们进一步确定Gata3是肾管中β-catenin功能的中心介质，并证明β-catenin/Gata3途径独立于其调节Ret表达的作用，可阻止细胞过早分化。总之，这些结果建立了一个遗传级联，其中Gata3作用于β-catenin的下游，但在Ret的上游，以防止异位输尿管出芽和肾管中过早的细胞分化。在人类中，肾脏的发育是在胚胎发育过程中，由一个简单的上皮结构——肾管——长出一个上皮芽——称为输尿管芽。输尿管芽迅速生长，形成树状分支，形成肾集管系统，而新出现的输尿管尖诱导肾元分化。肾脏发育过程中最重要的步骤之一是沿肾管定位单个输尿管芽，因为涉及该过程的基因突变导致严重的泌尿生殖畸形。在这项研究中，我们通过转基因小鼠发现Gata3蛋白是输尿管芽定位的关键调节因子。在小鼠中删除Gata3基因会导致多个肾脏在不合适的位置出现。我们发现这种缺陷是由肾管细胞对局部生长信号的反应的超敏性引起的。有趣的是，这种现象部分是由肾管细胞亚群的过早分化引起的。此外，我们报道了Wnt/β-catenin信号激活Gata3基因的遗传途径，而Gata3基因反过来正调控Ret基因。总之，我们介绍了一种小鼠模型系统，可用于研究影响泌尿生殖系统的人类出生缺陷。
Metanephric kidney induction critically depends on mesenchymal–epithelial interactions in the caudal region of the nephric (or Wolffian) duct. Central to this process, GDNF secreted from the metanephric mesenchyme induces ureter budding by activating the Ret receptor expressed in the nephric duct epithelium. A failure to regulate this pathway is believed to be responsible for a large proportion of the developmental anomalies affecting the urogenital system. Here, we show that the nephric duct-specific inactivation of the transcription factor gene Gata3 leads to massive ectopic ureter budding. This results in a spectrum of urogenital malformations including kidney adysplasia, duplex systems, and hydroureter, as well as vas deferens hyperplasia and uterine agenesis. The variability of developmental defects is reminiscent of the congenital anomalies of the kidney and urinary tract (CAKUT) observed in human. We show that Gata3 inactivation causes premature nephric duct cell differentiation and loss of Ret receptor gene expression. These changes ultimately affect nephric duct epithelium homeostasis, leading to ectopic budding of interspersed cells still expressing the Ret receptor. Importantly, the formation of these ectopic buds requires both GDNF/Ret and Fgf signaling activities. We further identify Gata3 as a central mediator of β-catenin function in the nephric duct and demonstrate that the β-catenin/Gata3 pathway prevents premature cell differentiation independently of its role in regulating Ret expression. Together, these results establish a genetic cascade in which Gata3 acts downstream of β-catenin, but upstream of Ret, to prevent ectopic ureter budding and premature cell differentiation in the nephric duct. In humans, kidney development originates during embryonic development by the sprouting of an epithelial bud—called the ureteric bud—from a simple epithelial structure—the nephric duct. The ureteric bud quickly grows and branches in a treelike fashion to form the kidney collecting duct system, while the emerging ureteric tips induce nephron differentiation. One of the most important steps during kidney development is the positioning of a single ureteric bud along the nephric duct, since mutations of genes implicated in this process lead to severe urogenital malformations. In this study, we identified the Gata3 protein as a crucial regulator of ureteric bud positioning by using genetically modified mice. Deleting the Gata3 gene in the mouse resulted in the development of multiple kidneys emerging at improper positions. We show that this defect was caused by a hypersensitivity of nephric duct cells in their response to local growth signals. Interestingly, this phenomenon was partly triggered by premature differentiation of a subset of nephric duct cells. Furthermore, we report a genetic pathway in which Wnt/β-catenin signaling activates the Gata3 gene, which in turn positively regulates the Ret gene. In summary, we introduce a mouse model system that can be used to study human birth defects affecting the urogenital system.
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