Expression of the androgen receptor and 5α-reductase type 2 in the developing human fetal penis and urethra

Numata

Proc. Natl. Acad. Sci. U.S.A.

et al. 2014

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

Section: Sexually Dimorphic Expression Of Mafb During Male-type Urethralmentioning

confidence: 99%

Sexually dimorphic expression ofMafbregulates masculinization of the embryonic urethral formation

Numata

Proc. Natl. Acad. Sci. U.S.A.

et al. 2014

“…By the eighth gestational week, a coordinated network of morphogenetic events, controlled by a network of signaling molecules, starts taking place even before the sexually dimorphic hormonally controlled phase. 4 These processes are orchestrated by the urethral plate epithelium (UPE), at the GT, which has a polarizing activity. 5,6 Sonic hedgehog (Shh), expressed at the UPE, is required for outgrowth and patterning of the genital tubercle and mice with a targeted deletion of shh have penile and clitoral agenesis.…”

Section: Introductionmentioning

confidence: 99%

FGFR2, FGF8, FGF10 and BMP7 as candidate genes for hypospadias

et al. 2007

Hypospadias is a common malformation, which results from failure of urethral tube closure, and whose molecular mechanisms are still largely unknown. The normal genital development is orchestrated by the urethral plate epithelium (UPE), at the genital tubercle (GT), which has polarizing activity, controlling a network of epithelial-mesenchymal interactions, which, when disturbed, may lead to hypospadias. Homeobox proteins (HOXs), fibroblast growth factors (FGFs) and bone morphogenic proteins (BMPs) are essential in this process. Hypospadias in the Hoxa13 À/À mice occurs as a result of the combined loss of Fgf8 and Bmp7 expression in the UPE. In both Fgf10 and Fgfr2 deficient mutant hypospadic male mice, cell proliferation is arrested prematurely and the maturation of the urethral epithelium is disrupted. Fgf8, Fgf10, and their receptor Fgfr2 are downstream targets of androgens (AR) during external genital development, an important fact given the pivotal role of AR in male sex differentiation. Therefore, we examined FGFR2, FGF10, FGF8, and BMP7 as candidate genes for hypospadias. DNA from 60 boys with familial, isolated, hypospadias was screened for mutations in FGFR2, FGF10, FGF8, and BMP7 genes, using DHPLC and DNA sequence analysis. The sequence variations c. and, c.550 þ 27C4T, c.727 þ 180T4G, c.830T4C (p.Me186Thr), and c.2454C4T in FGFR2 were found uniquely in patients with hypospadias, as compared with 96 controls. No genetic variant in the other genes was detected. These results indicate that mutations are rare in FGF8 and FGFR2 in hypospadias, but gene variants may influence the risk.

“…Notably, the early differentiation and morphogenesis of male reproductive organs corresponds to the testosterone surge by fetal Leydig cells that occurs at about 12 weeks of gestation in humans (Williams-Ashman & Reddi 1991, George & Wilson 1994, Klonisch et al 2004 and at late gestation and early neonatal period in rodents (Ward & Weisz 1984, El-Gehani et al 1998. Alterations in androgenic activity during the critical period of differentiation, resulting from abnormalities in testosterone, 5a-reductase, or androgen receptor, cause maldevelopment of internal and external male genitalia, including hypospadias and shorter penis (Gray et al 2001, Sultan et al 2001, Kim et al 2002, Foster & Harris 2005. In a situation where androgen receptors are inherently lacking, such as in androgen insensitivity syndrome, external genitalia develop as those of females (Wiener et al 1997, Regadera et al 1999, Hiort 2000.…”

Section: Introductionmentioning

confidence: 99%

Estrogen receptor-α mediates estrogen-inducible abnormalities in the developing penis

Goyal

Braden²,

Cooke³

et al. 2007

Reproduction

Previously, we reported an association between estrogen receptor-a (ERa) upregulation and detrimental effects of neonatal diethylstilbestrol (DES) exposure in the rat penis. The objective of this study was to employ the ERa knockout (ERaKO) mouse model to test the hypothesis that ERa mediates DES effects in the developing penis. ERaKO and wild-type C57BL/6 mice received oil or DES at a dose of 0.2 mg/pup per day (0.1 mg/kg) on alternate days from postnatal days 2 to 12. Fertility was tested at 80-240 days of age and tissues were examined at 96-255 days of age. DES caused malformation of the os penis, significant reductions in penile length, diameter, and weight, accumulation of fat cells in the corpora cavernosa penis, and significant reductions in weight of the bulbospongiosus and levator ani muscles in wild-type mice. Conversely, ERaKO mice treated with DES developed none of the above abnormalities. While nine out of ten male mice sired pups in the wild-type/control group, none did in the wildtype/DES group. ERaKO mice, despite normal penile development, are inherently infertile. Both plasma and intratesticular testosterone levels were unaltered in the DES-treated wild-type or DES-treated ERaKO mice when compared with controls, although testosterone concentration was much higher in the ERaKO mice. Hence, the resistance of ERaKO mice to developing penile abnormalities provides unequivocal evidence of an obligatory role for ERa in mediating the harmful effects of neonatal DES exposure in the developing penis.