vHNF1 functions in distinct regulatory circuits to control ureteric bud branching and early nephrogenesis
vHNF1 functions in distinct regulatory circuits to control ureteric bud branching and early nephrogenesis
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DOI：
10.1242/dev.042226
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发表时间：
2010-01-15
期刊：
影响因子：
4.6
通讯作者：
Cereghini, Silvia
中科院分区：
文献类型：
--
作者：
Lokmane, Ludmilla;Heliot, Claire;Cereghini, Silvia
小鼠后肾发育始于通过后肾间质信号从沃尔夫管尾部诱导输尿管芽（UB）。当UB经历分支形态发生以产生整个尿液收集系统和输尿管时，UB尖端分泌的因子诱导周围的间充质细胞转化为上皮细胞并形成肾单位，即肾脏的功能单位。因此，上皮分支形态发生和肾发生是紧密协调的。这些过程中的任何一个的缺陷都会导致严重的肾脏表型，从发育不全到完全发育不全。然而，基本的监管网络仅得到部分阐明。在这里，我们确定转录因子 vHNF1 (HNF1 beta) 是这些早期发育事件的关键调节因子。 vHNF1 最初参与 UB 生长和随后分支的计时，也是肾管上皮维持、苗勒管形成和早期肾发生所必需的。镶嵌分析进一步表明，vHNF1 在获得专门的尖端结构域和分支形态发生方面存在细胞自主需求。 vHNF1 至少部分通过直接控制涉及早期肾脏发育不同方面的关键调节分子来发挥这些复杂的功能。值得注意的是，直接作用于 Wnt9b 上游的 vHNF1 似乎在肾发生起始的间充质-上皮转变中协调 Wnt 信号传导作用。这些结果表明，vHNF1 是一种重要的转录调节因子，除了在正常导管形态发生中已知的后期功能外，它还在泌尿生殖发育的最早阶段发挥着至关重要的作用，并为控制事件的调节回路提供了新的见解。
Mouse metanephric kidney development begins with the induction of the ureteric bud (UB) from the caudal portion of the Wolffian duct by metanephric mesenchymal signals. While the UB undergoes branching morphogenesis to generate the entire urinary collecting system and the ureter, factors secreted by the UB tips induce surrounding mesenchymal cells to convert into epithelia and form the nephrons, the functional units of the kidney. Epithelial branching morphogenesis and nephrogenesis are therefore tightly orchestrated; defects in either of these processes lead to severe kidney phenotypes ranging from hypoplasia to complete aplasia. However, the underlying regulatory networks have been only partially elucidated. Here, we identify the transcription factor vHNF1 (HNF1 beta) as a crucial regulator of these early developmental events. Initially involved in timing outgrowth of the UB and subsequent branching, vHNF1 is also required for nephric duct epithelial maintenance, Mullerian duct formation and early nephrogenesis. Mosaic analyses further suggest a cell-autonomous requirement for vHNF1 in the acquisition of a specialized tip domain and branching morphogenesis. vHNF1 exerts these intricate functions at least in part through the direct control of key regulatory molecules involved in different aspects of early kidney development. Notably, vHNF1 acting directly upstream of Wnt9b appears to orchestrate Wnt signaling action in the mesenchymal-epithelial transitions underlying the initiation of nephrogenesis. These results demonstrate that vHNF1 is an essential transcriptional regulator that, in addition to the known later functions in normal duct morphogenesis, plays a crucial role during the earliest stages of urogenital development and provide novel insights into the regulatory circuits controlling events.