Androgen Regulation of Prostate Morphoregulatory Gene Expression:Fgf10-Dependent and -Independent Pathways

Abstract

Androgens are essential and sufficient for prostate gland morphogenesis; however, the downstream gene targets that mediate this action are unclear. To identify androgen-regulated genes involved in prostate development, we used short-term organ culture and examined the effect of testosterone on the expression of several critical prostate morphoregulatory genes. Rat ventral prostates (VP) and lateral prostates (LP) were collected at birth, and contralateral lobes were cultured for 18 h in the presence or absence of 10 nM testosterone with or without OH-flutamide to block residual androgens. Gene expression was quantitated using real-time RT-PCR. Although expression of Fgf10, Nkx3.1, and Ptc was increased in both prostate lobes, other genes were regulated by testosterone in a lobe-specific manner. This included up-regulation of epithelial genes FgfR2iiib, Shh, Hoxb13, and Bmp7 in the VP specifically and down-regulation of mesenchymal genes Wnt5a (VP) and Bmp4 (LP). Thus, in addition to stimulation of homeobox genes and paracrine-acting growth factors, androgens may positively regulate prostatic development through suppression of growth inhibitory genes. Because previous studies revealed a similar gene regulation pattern in response to exogenous Fgf10, experiments were performed to identify androgen-regulated genes mediated through Fgf10 signaling. Short-term VP and LP cultures with FgfR antagonist PD173074 and Mek inhibitor U0126 identified epithelial Shh and Hoxb13 up-regulation by androgens to be Fgf10-dependent. We propose that androgen regulation of prostate development is mediated through positive and negative regulation of multiple morphoregulatory genes acting in combination through complex gene networks. Lobe-specific responses may provide a developmental basis for prostate gland heterogeneity.

Role of FGFR2-signaling in the pathogenesis of acne

“…86 Importantly, recent evidence supports the view that androgens regulate the expression of prostatic morphoregulatory genes including upregulation of FGF10 expression and FGF10-signaling in the developing prostate. 86 Furthermore, androgens increased FGFR2b in the ventral rat prostate, thereby increasing epithelial cell responsiveness for its ligands FGF7 and FGF10. 86,87 Shh, which is an epithelial secreted morphogen, essential for prostate development, increased after testosterone stimulation as well.…”

“…86 Furthermore, androgens increased FGFR2b in the ventral rat prostate, thereby increasing epithelial cell responsiveness for its ligands FGF7 and FGF10. 86,87 Shh, which is an epithelial secreted morphogen, essential for prostate development, increased after testosterone stimulation as well. 86 In the rat prostate, androgens regulate the expression of epithelial morphoregulatory genes of the gland, where FGF10 has been shown to be the proximate regulator of steroid action.…”

“…85 Short-term ventral prostate and lateral prostate cultures with FGFR antagonist PD173074 and Mek inhibitor U0126 identified epithelial sonic hedgehog (Shh) and Hoxb13 upregulation by androgens to be FGF10-dependent. 86 Androgens regulate prostate morphoregulatory gene expression by FGF10-dependent and FGF10-independent mechanisms. 86 Importantly, recent evidence supports the view that androgens regulate the expression of prostatic morphoregulatory genes including upregulation of FGF10 expression and FGF10-signaling in the developing prostate.…”

“…86 Androgens regulate prostate morphoregulatory gene expression by FGF10-dependent and FGF10-independent mechanisms. 86 Importantly, recent evidence supports the view that androgens regulate the expression of prostatic morphoregulatory genes including upregulation of FGF10 expression and FGF10-signaling in the developing prostate. 86 Furthermore, androgens increased FGFR2b in the ventral rat prostate, thereby increasing epithelial cell responsiveness for its ligands FGF7 and FGF10.…”

Voie de signalisation Sonic Hedgehog et impact des glucocorticoïdes sur le cerveau en développement

“…À l'inverse, les oestrogènes diminuent l'expression de Ihh et Dhh dans l'utérus [30]. Les androgènes et les oestrogènes sont antagonistes : ils induisent et inhibent respectivement l'expression de Shh au cours du développement prostatique [31,32]. Ainsi, les hormones stéroïdes jouent des rôles variables sur la voie de signalisation Shh selon le type d'organe et le type d'hormone considéré.…”