Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University, Kimiidera 811-1, Wakayama City, Wakayama, 641-8509, Japan.
Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Tokyo, 125-8585, Japan.
Differentiation. 2019 Nov-Dec;110:29-35. doi: 10.1016/j.diff.2019.08.004. Epub 2019 Sep 11.
Development of external genitalia (ExG) has been a topic of long mystery in the field of organogenesis research. Early stage male and female of mouse embryos develop a common genital tubercle (GT) in the perineum whose outgrowth extends distally from the posterior cloacal regions. Concomitant with GT outgrowth, the cloaca is divided into urogenital sinus and anorectum by urorectal septum (URS) internally. The outgrowth of the GT is associated with the formation of endodermal epithelial urethral plate (UP) attached to the ventral epidermis of the GT. Such a common developmental phase is observed until around embryonic day 15.5 (E15.5) morphologically in mouse embryogenesis. Various growth factor genes, such as Fibroblast growth factor (Fgf) and Wnt genes are expressed and function during GT formation. Since the discovery of key growth factor signals and several regulatory molecules, elucidation of their functions has been achieved utilizing mouse developmental models, conditional gene knockout mouse and in vitro culture. Analyses on the phenotypes of such mouse models have revealed that several growth factor families play fundamental roles in ExG organogenesis based on the epithelial-mesenchymal interaction (EMI). More recently, EMI between developing urethral epithelia and its bilateral mesenchyme of later stages is also reported during subsequent stage of androgen-dependent male-type urethral formation in the mouse embryo. Mafb, belonging to AP-1 family and a key androgen-responsive mesenchymal gene, is identified and starts to be expressed around E14.5 when masculinization of the urethra is initiated. Mesenchymal cell condensation and migration, which are regulated by nonmuscle myosin, are shown to be essential process for masculinization. Hence, studies on EMI at various embryonic stages are important not only for early but also for subsequent masculinization of the urethra. In this review, a dynamic mode of EMI for both early and late phases of ExG development is discussed.
外生殖器（ExG）的发育一直是器官发生研究领域的一个长期谜团。早期的雄性和雌性小鼠胚胎在会阴部发育出一个共同的生殖器结节（GT），其延伸从后肛区向远端延伸。随着 GT 的延伸，尿直肠隔（URS）将肛内部分为尿生殖窦和肛直肠。GT 的延伸与内胚层上皮尿道板（UP）的形成有关，该 UP 附着在 GT 的腹侧表皮上。在形态学上，这种共同的发育阶段在小鼠胚胎发生中一直持续到大约 15.5 天（E15.5）。在 GT 形成过程中，各种生长因子基因，如成纤维细胞生长因子（Fgf）和 Wnt 基因，都有表达并发挥作用。自从关键生长因子信号和几个调节分子被发现以来，利用小鼠发育模型、条件性基因敲除小鼠和体外培养，已经阐明了它们的功能。对这些小鼠模型的表型分析表明，几种生长因子家族基于上皮-间充质相互作用（EMI）在外生殖器器官发生中发挥着基本作用。最近，在雄性型尿道形成的小鼠胚胎随后的阶段中，也有报道称，在发育中的尿道上皮与其双侧间充质之间也存在 EMI。Mafb 属于 AP-1 家族，是一种关键的雄激素反应性间充质基因，在尿道开始雄性化的 E14.5 左右被鉴定并开始表达。由非肌肉肌球蛋白调节的间充质细胞凝聚和迁移被证明是雄性化所必需的过程。因此，在不同胚胎阶段研究 EMI 不仅对早期而且对尿道的随后雄性化都很重要。在这篇综述中，讨论了 ExG 早期和晚期发育中 EMI 的动态模式。
