The role of p63 in embryonic external genitalia outgrowth in mice
The role of p63 in embryonic external genitalia outgrowth in mice
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DOI：
10.1111/dgd.12840
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发表时间：
2023-02-02
影响因子：
2.5
通讯作者：
Miyagawa，Shinichi
中科院分区：
文献类型：
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作者：
Tanaka，Kosei;Matsumaru，Daisuke;Miyagawa，Shinichi
胚胎的外生殖器（生殖结节[GT]）从泄殖腔中突出，并随着泄殖腔的发育而生长。个别基因的功能和基因敲除表型在GT的发展已被广泛分析，然而，这些基因之间的相互作用还没有完全理解。在这项研究中，我们研究了p63的作用，重点是它与Shh-Wnt/Ctnnb 1-Fgf 8通路的相互作用，这是一个已知在GT生长中发挥作用的信号网络。在E11.5时，GT的上皮组织中表达p63，并且GT的远端主要表达Δ Np 63 α亚型。在p63基因敲除胚胎中，GTs的Shh基因表达正常，但CTNNB 1蛋白和Fgf 8基因在远端尿道上皮中的表达降低或缺失。CTNNB 1在p63缺失胚胎中的组成型表达恢复了Fgf 8表达，伴随着小的芽结构发育;然而，E13.5不能维持这种芽结构，此时突变的GT表现出严重的异常，显示出分裂的形状，具有出血性泄殖腔。因此，p63是信号通路的关键组成部分，其通过确保泄殖腔上皮的结构完整性来促进远端尿道上皮中Fgf 8的表达并有助于GT的生长。总之，我们认为p63在外生殖器发育的信号网络中起着至关重要的作用。
Embryonic external genitalia (genital tubercle [GT]) protrude from the cloaca and outgrow as cloacal development progresses. Individual gene functions and knockout phenotypes in GT development have been extensively analyzed; however, the interactions between these genes are not fully understood. In this study, we investigated the role of p63, focusing on its interaction with the Shh–Wnt/Ctnnb1–Fgf8 pathway, a signaling network that is known to play a role in GT outgrowth. p63 was expressed in the epithelial tissues of the GT at E11.5, and the distal tip of the GT predominantly expressed the ΔNp63α isoform. The GTs inp63knockout embryos had normalShhexpression, but CTNNB1 protein andFgf8gene expression in the distal urethral epithelium was decreased or lost. Constitutive expression of CTNNB1 inp63‐null embryos restoredFgf8expression, accompanied by small bud structure development; however, such bud structures could not be maintained by E13.5, at which point mutant GTs exhibited severe abnormalities showing a split shape with a hemorrhagic cloaca. Therefore, p63 is a key component of the signaling pathway that triggersFgf8expression in the distal urethral epithelium and contributes to GT outgrowth by ensuring the structural integrity of the cloacal epithelia. Altogether, we propose that p63 plays an essential role in the signaling network for the development of external genitalia.