Lin Congxing, Yin Yan, Veith G Michael, Fisher Alexander V, Long Fanxin, Ma Liang
Division of Dermatology, Washington University School of Medicine, 660 S. Euclid Avenue, St Louis, MO 63110, USA.
Development. 2009 Dec;136(23):3959-67. doi: 10.1242/dev.039768.
Genital tubercle (GT) initiation and outgrowth involve coordinated morphogenesis of surface ectoderm, cloacal mesoderm and hindgut endoderm. GT development appears to mirror that of the limb. Although Shh is essential for the development of both appendages, its role in GT development is much less clear than in the limb. Here, by removing Shh at different stages during GT development in mice, we demonstrate a continuous requirement for Shh in GT initiation and subsequent androgen-independent GT growth. Moreover, we investigated the Hh responsiveness of different tissue layers by removing or activating its signal transducer Smo with tissue-specific Cre lines, and established GT mesenchyme as the primary target tissue of Shh signaling. Lastly, we showed that Shh is required for the maintenance of the GT signaling center distal urethral epithelium (dUE). By restoring Wnt-Fgf8 signaling in Shh(-/-) cloacal endoderm genetically, we revealed that Shh relays its signal partly through the dUE, but regulates Hoxa13 and Hoxd13 expression independently of dUE signaling. Altogether, we propose that Shh plays a central role in GT development by simultaneously regulating patterning of the cloacal field and supporting an outgrowth signal.
生殖结节（GT）的起始和生长涉及表面外胚层、泄殖腔中胚层和后肠内胚层的协调形态发生。GT的发育似乎与肢体的发育相似。尽管Shh对两者的发育都至关重要，但其在GT发育中的作用远不如在肢体发育中明确。在这里，通过在小鼠GT发育的不同阶段去除Shh，我们证明了在GT起始和随后的雄激素非依赖性GT生长过程中对Shh的持续需求。此外，我们通过用组织特异性Cre系去除或激活其信号转导器Smo来研究不同组织层对Hh的反应性，并确定GT间充质是Shh信号传导的主要靶组织。最后，我们表明Shh是维持GT信号中心远端尿道上皮（dUE）所必需的。通过在基因上恢复Shh（-/-）泄殖腔内胚层中的Wnt-Fgf8信号，我们发现Shh部分通过dUE传递其信号，但独立于dUE信号调节Hoxa13和Hoxd13的表达。总之，我们提出Shh通过同时调节泄殖腔区域的模式形成和支持生长信号在GT发育中起核心作用。
