Trps1 Functions Downstream of Bmp7 in Kidney Development
Trps1 Functions Downstream of Bmp7 in Kidney Development
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DOI：
10.1681/asn.2008091020
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发表时间：
2009-11-01
影响因子：
13.6
通讯作者：
Muragaki, Yasuteru
中科院分区：
文献类型：
--
作者：
Gai, Zhibo;Zhou, Gengyin;Muragaki, Yasuteru
在胚胎发育过程中，肺、肠道、肾脏和其他组织的间质表达Trps1，这是GATA型转录因子家族中的一个非典型成员。我们以前的工作表明，Trps1可能作用于骨形态发生蛋白7(Bmp7)的下游，骨形态发生蛋白7是正常肾脏发育所必需的。为了研究Trps1在早期肾脏发育中的作用，我们建立了Trps1缺陷小鼠，并检查了它们的肾脏组织学。与野生型小鼠相比，Trps1基因缺陷的新生小鼠肾小管和肾小球较少，肾间质扩张，并有大量未诱导的后肾间充质细胞，导致肾单位较少。在野生型肾脏中，Trps1表达存在于输尿管芽、帽间充质和肾小泡中，而在Bmp7基因缺陷的肾脏中，Trps1几乎不表达。此外，Trps1缺失的肾脏具有低水平的Pax2和Wt1，这是浓缩间充质细胞的标志，这表明Trps1的缺失影响了帽间充质细胞向肾小泡的分化。在培养的后肾间充质细胞中，Bmp7诱导Trps1和E-cadherin的表达，下调Vimentin的表达。用小干扰RNA敲除Trps1可以抑制Bmp7诱导的间充质向上皮细胞的转变。最后，Wnt9b和Wnt4的整体原位杂交显示，Trps1基因缺陷小鼠的肾脏中存在输尿管芽的长时间分支和稀疏的帽间充质。综上所述，这些发现表明，正常的肾单位的形成需要Trps1，它在早期肾脏发育过程中介导间充质向上皮的转变和输尿管芽分支。
During embryonic development, the mesenchyme of the lungs, gut, kidneys, and other tissues expresses Trps1, an atypical member of the GATA-type family of transcription factors. Our previous work suggested the possibility that Trps1 acts downstream of bone morphogenic protein 7 (Bmp7), which is essential for normal renal development. To examine the role of Trps1 during early renal development, we generated Trps1-deficient mice and examined their renal histology. Compared with wild-type mice, Trps1-deficient newborn mice had fewer tubules and glomeruli, an expanded renal interstitium, and numerous uninduced metanephric mesenchymal cells, which resulted in fewer nephrons. In wild-type kidneys, Trps1 expression was present in ureteric buds, cap mesenchyme, and renal vesicles, whereas Trps1 was virtually absent in Bmp7-deficient kidneys. Furthermore, Trps1-deficient kidneys had low levels of Pax2 and Wt1, which are markers of condensed mesenchymal cells, suggesting that a lack of Trps1 affects the differentiation of cap mesenchyme to renal vesicles. In cultured metanephric mesenchymal cells, Bmp7 induced Trps1 and E-cadherin and downregulated vimentin. Knockdown of Trps1 with small interference RNA inhibited this Bmp7-induced mesenchymal-to-epithelial transition. Last, whole-mount in situ hybridization of Wnt9b and Wnt4 demonstrated prolonged branching of ureteric buds and sparse cap mesenchyme in the kidneys of Trps1-deficient mice. Taken together, these findings suggest that normal formation of nephrons requires Trps1, which mediates mesenchymal-to-epithelial transition and ureteric bud branching during early renal development.