Stage-dependent function of Wnt5a during male external genitalia development
Stage-dependent function of Wnt5a during male external genitalia development
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DOI：
10.1111/cga.12438
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发表时间：
2021-07-21
影响因子：
1.3
通讯作者：
Yamada, Gen
中科院分区：
文献类型：
--
作者：
Alcantara, Mellissa C.;Suzuki, Kentaro;Yamada, Gen
小鼠外生殖器发育涉及多种信号通路调控下的多个发育过程。 Wnt5a 是主要的 Wnt 配体之一，是四肢、下颌骨和外生殖器等器官发育的重要调节因子。 Wnt5a 信号传导缺陷与 Robinow 综合征有关，Robinow 综合征是一种遗传性疾病，男性患者会出现小阴茎和尿道管形成缺陷。尽管 Wnt5a 是胚胎外生殖器生长过程中细胞增殖所必需的，但其在尿道管形成中的作用尚不清楚。在这里，我们表明 Wnt5a 有助于尿道管的形成以及外生殖器的生长。 Wnt5a在胚胎外生殖器间充质中表达，间充质特异性条件性Wnt5a基因敲除小鼠会导致尿道下裂样尿道缺陷。 E10.5 处 Wnt5a 的早期缺失显示出外生殖器生长和尿道管形成的严重缺陷，以及细胞增殖的减少。在随后的 Wnt5a (E13.5) 定时删除过程中，严重的尿道管缺陷持续存在。进一步的分析表明，Wnt5a 的缺失会破坏细胞极性，并导致磷酸化肌球蛋白轻链和粘着斑蛋白纽蛋白的减少。总而言之，这些结果表明，在男性外生殖器发育过程中，Wnt5a 以阶段依赖性方式协调细胞增殖并指导细胞迁移。此外，Wnt5a 可以调节细胞极性、粘着斑形成和细胞收缩性，从而导致男性型尿道形成期间的定向细胞迁移，其方式在其他器官融合事件中尚未报道。
External genitalia development in mice involves multiple developmental processes under the regulation of various signaling pathways. Wnt5a, one of the major Wnt ligands, is a crucial developmental regulator of outgrowing organs such as the limb, the mandible, and the external genitalia. Defects in Wnt5a signaling have been linked to Robinow syndrome, a genetic disorder in which male patients manifest a micropenis and defective urethral tube formation. Whereas Wnt5a is required for cell proliferation during embryonic external genitalia outgrowth, its role for urethral tube formation has yet to be understood. Here, we show that Wnt5a contributes to urethral tube formation as well as external genitalia outgrowth. Wnt5a is expressed in the embryonic external genitalia mesenchyme, and mesenchymal-specific conditional Wnt5a knockout mice resulted in hypospadias-like urethral defects. Early deletion of Wnt5a at E10.5 showed severe defects in both external genitalia outgrowth and urethral tube formation, along with reduced cell proliferation. The severe urethral tube defect persisted during later timing deletion of Wnt5a (E13.5). Further analyses revealed that loss of Wnt5a disrupted cell polarity and led to a reduction of the phosphorylated myosin light chain and the focal adhesion protein, vinculin. Altogether, these results suggest that Wnt5a coordinates cell proliferation and directed cell migration in a stage-dependent manner during male external genitalia development. Furthermore, Wnt5a may regulate cell polarity, focal adhesion formation, and cell contractility, leading to directed cell migration during male-type urethral formation in a manner that has not been reported in other organ fusion events.