Sexually dimorphic expression of Mafb regulates masculinization of the embryonic urethral formation
Sexually dimorphic expression of Mafb regulates masculinization of the embryonic urethral formation
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DOI：
10.1073/pnas.1413273111
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发表时间：
2014-11-18
影响因子：
11.1
通讯作者：
Yamada, Gen
中科院分区：
文献类型：
--
作者：
Suzuki, Kentaro;Numata, Tomokazu;Yamada, Gen
外生殖器的男性化是男性生殖系统形成的一个重要过程。这种男性化的突出特征是尿道的器官大小和性别分化。虽然雄激素是男性化的关键诱导剂，但雄激素控制下的调节机制尚不清楚。在这里，我们通过鉴定v-maf禽肌肉腱神经纤维肉瘤癌基因同源基因B （Mafb）来解决这个长期存在的问题，即雄激素是如何诱导胚胎外生殖器雄性化的。mafeb在男性生殖器结节（GT）的间质中有显著表达。在雌性gt的间质中很少检测到MAFB的表达。然而，暴露于外源雄激素可诱导其在雌性GTs中的间质表达。此外，在雄激素受体（Ar） KO小鼠的雄性GTs中，MAFB的表达显著下调，表明Ar信号是其表达所必需的。我们发现mabb KO男性GTs表现出有缺陷的胚胎尿道形成，从而深入了解人类常见的先天性尿道下裂异常。然而，mabb KO雄性GTs的大小与野生型雄性相似。此外，雄激素治疗不能诱导mabb KO小鼠尿道中GTs的雄性化。目前的结果表明，mafeb是雄激素诱导的，胚胎尿道雄性化的两性调节剂。
Masculinization of external genitalia is an essential process in the formation of the male reproductive system. Prominent characteristics of this masculinization are the organ size and the sexual differentiation of the urethra. Although androgen is a pivotal inducer of the masculinization, the regulatory mechanism under the control of androgen is still unknown. Here, we address this longstanding question about how androgen induces masculinization of the embryonic external genitalia through the identification of the v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (Mafb) gene. Mafb is expressed prominently in the mesenchyme of male genital tubercle (GT), the anlage of external genitalia. MAFB expression is rarely detected in the mesenchyme of female GTs. However, exposure to exogenous androgen induces its mesenchymal expression in female GTs. Furthermore, MAFB expression is prominently down-regulated in male GTs of androgen receptor (Ar) KO mice, indicating that AR signaling is necessary for its expression. It is revealed that Mafb KO male GTs exhibit defective embryonic urethral formation, giving insight into the common human congenital anomaly hypospadias. However, the size of Mafb KO male GTs is similar with that of wild-type males. Moreover, androgen treatment fails to induce urethral masculinization of the GTs in Mafb KO mice. The current results provide evidence that Mafb is an androgen-inducible, sexually dimorphic regulator of embryonic urethral masculinization.