Kidney development in the absence of Gdnf and Spry1 requires Fgf10.
Kidney development in the absence of Gdnf and Spry1 requires Fgf10.
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DOI：
10.1371/journal.pgen.1000809
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发表时间：
2010-01-15
期刊：
影响因子：
4.5
通讯作者：
Costantini F
中科院分区：
文献类型：
--
作者：
Michos O;Cebrian C;Hyink D;Grieshammer U;Williams L;D'Agati V;Licht JD;Martin GR;Costantini F
在小鼠和人的肾脏发育过程中，GDNF信号通过Ret受体酪氨酸激酶(RTK)是输尿管芽(UB)分支形态发生所必需的。此外，许多其他导致肾发育不全的突变基因通过GDNF/RET途径发挥作用。因此，RET信号被认为在肾脏器官发生中起核心作用。在这里，我们通过寻找肾脏在缺乏GDNF和Ret的情况下发育的条件，重新检查GDNF和Ret功能的独特程度。我们发现，在缺乏负调控因子Spry1、GDNF和Ret的情况下，广泛的肾脏发育不再需要它们。GDnF−/−；Spry1−/−或Ret−/−；Spry1−/−双突变体发育成大肾，具有正常的输尿管、高度分支的集合管、广泛的肾发生和正常的组织结构。然而，尽管有广泛的分支，UB在分支间距、角度和频率方面都会发生变化。在缺乏GDNF和Spry1的情况下，UB分支需要Fgf10(通常作用很小)，因为GDnf−/−中即使只有一个拷贝的Fgf10被移除；Spry1−/−突变会导致输尿管和肾脏发育完全失败。与GDNF或Ret突变相反，由于缺乏转录因子ETV4和ETV5而导致的肾脏发育不全不能通过移除Spry1来挽救，这与它们在RET和FGFRs下游的作用一致。这表明，对于肾脏发育的许多方面，RTK的积极信号和SPRY1对该信号的负面调节之间的平衡比GDNF的具体作用更为关键。当SPRY1不存在时，包括FGF10在内的其他信号可以执行GDNF的许多功能。但GDNF/RET信号在决定正常分支模式方面具有明显独特的功能。与GDNF或FGF10不同，ETV4和ETV5代表RTK信令网络中的关键节点，其不能通过减少对上行信号的负调节而被绕过。肾脏的发育需要分泌蛋白GDNF，它通过其细胞受体RET发出信号，促进集合管系统的前体输尿管芽的生长和分支。转录因子ETV4和ETV5调节基因表达以响应GDNF。我们报告，删除RET下游的反馈抑制剂Spry1，可以在很大程度上挽救缺乏GDNF或RET的小鼠的肾脏发育，尽管在那些缺乏ETV4和ETV5的小鼠中并非如此。因此，在没有SPRY1的情况下，GDNF和RET变得可有可无，因为它们的作用主要由其他信号和受体承担，而ETV4和ETV5仍然是不可或缺的。我们认为FGF10是在缺乏GDNF/RET信号和SPRY1负调控的情况下导致肾脏发育的信号。但在−/−、Spry1−/−和Ret−/−、Spry1−/−肾中，当输尿管芽广泛分支时，其分支模式被严重扰乱。这表明GDNF在输尿管芽形态形成中具有独特的功能。
GDNF signaling through the Ret receptor tyrosine kinase (RTK) is required for ureteric bud (UB) branching morphogenesis during kidney development in mice and humans. Furthermore, many other mutant genes that cause renal agenesis exert their effects via the GDNF/RET pathway. Therefore, RET signaling is believed to play a central role in renal organogenesis. Here, we re-examine the extent to which the functions of Gdnf and Ret are unique, by seeking conditions in which a kidney can develop in their absence. We find that in the absence of the negative regulator Spry1, Gdnf, and Ret are no longer required for extensive kidney development. Gdnf−/−;Spry1−/− or Ret−/−;Spry1−/− double mutants develop large kidneys with normal ureters, highly branched collecting ducts, extensive nephrogenesis, and normal histoarchitecture. However, despite extensive branching, the UB displays alterations in branch spacing, angle, and frequency. UB branching in the absence of Gdnf and Spry1 requires Fgf10 (which normally plays a minor role), as removal of even one copy of Fgf10 in Gdnf−/−;Spry1−/− mutants causes a complete failure of ureter and kidney development. In contrast to Gdnf or Ret mutations, renal agenesis caused by concomitant lack of the transcription factors ETV4 and ETV5 is not rescued by removing Spry1, consistent with their role downstream of both RET and FGFRs. This shows that, for many aspects of renal development, the balance between positive signaling by RTKs and negative regulation of this signaling by SPRY1 is more critical than the specific role of GDNF. Other signals, including FGF10, can perform many of the functions of GDNF, when SPRY1 is absent. But GDNF/RET signaling has an apparently unique function in determining normal branching pattern. In contrast to GDNF or FGF10, Etv4 and Etv5 represent a critical node in the RTK signaling network that cannot by bypassed by reducing the negative regulation of upstream signals. Kidney development requires the secreted protein GDNF, which signals via its cellular receptor RET to promote growth and branching of the ureteric bud, the progenitor of the collecting duct system. The transcription factors ETV4 and ETV5 regulate gene expression in response to GDNF. We report that deleting Spry1, a feedback inhibitor downstream of RET, largely rescues kidney development in mice lacking GDNF or RET, although not in those lacking ETV4 and ETV5. Thus, GDNF and RET become dispensable in the absence of SPRY1, when their roles can be largely assumed by other signals and receptors, while ETV4 and ETV5 remain indispensible. We identify FGF10 as the signal responsible for kidney development in the combined absence of GDNF/RET signaling and SPRY1 negative regulation. But while the ureteric bud branches extensively in Gdnf−/−;Spry1−/− and Ret−/−;Spry1−/− kidneys, its pattern of branching is severely perturbed. This points to a unique function of GDNF in ureteric bud patterning.
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