Sexually dimorphic expression ofMafbregulates masculinization of the embryonic urethral formation

Abstract

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.Mafb | masculinization | urethra | hypospadias | androgen receptor

Androgen Regulates Mafb Expression Through its 3′UTR During Mouse Urethral Masculinization

“…We identified MAFB as one of the essential masculinization factors for urethral masculinization (6). However, the mechanisms by which AR-mediated signaling regulates its expression were unclear.…”

“…The urethra is incorporated into the glans in males by androgen action (3,4). Androgen signaling in the mesenchyme adjacent to the urethra is essential for embryonic urethral masculinization (5,6). Thus, urethral masculinization is a useful model for understanding of the mechanisms underlying hormone-dependent sexual differentiation.…”

“…Moreover, Mafb KO male GTs exhibited hypospadias-like defects in the urethra. Therefore, MAFB is an androgen-inducible, sexually dimorphic regulator of embryonic urethral masculinization (6). However, it remains unclear how androgen regulates Mafb expression.…”

Androgen Regulates Dimorphic F-Actin Assemblies in the Genital Organogenesis

“…1 A, B). Androgen signaling in the mesenchyme around the urethra (hereafter designated as UMCs) is essential for the formation of the penile urethra [Miyagawa et al, 2009;Suzuki et al, 2014]. Intriguingly, cellular morphology of UMCs was significantly different between sexes ( Fig.…”

“…Several genes have been identified as essential regulators of male-and female-type reproductive organ formation [Miyagawa et al, 2009;Chen et al, 2010;Chen et al, 2011;Suzuki et al, 2014]. However, the cel-lular level of differentiation, particularly mesenchymal characters in the male-and female-type genital organ formation processes remain unelucidated.…”