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

Abstract

External genitalia are prominent organs showing hormone-dependent sexual differentiation. Androgen is an essential regulator of masculinization of the genital tubercle, which is the anlage of external genitalia. We have previously shown that v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) is an androgen-inducible regulator of embryonic urethral masculinization in mice. However, it remains unclear how androgen regulates Mafb expression. The current study suggests that the Mafb 3' untranslated region (UTR) is an essential region for its regulation by androgen. We identified 2 functional androgen response elements (AREs) in Mafb 3'UTR. Androgen receptor is bound to such AREs in 3'UTR during urethral masculinization. In addition to 3'UTR, Mafb 5'UTR also showed androgen responsiveness. Moreover, we also demonstrated that β-catenin, one of genital tubercle masculinization factors, may be an additional regulator of Mafb expression during urethral masculinization. This study provides insights to elucidate mechanisms of gene regulation through AREs present in Mafb 3'UTR for a better understanding of the processes of urethral masculinization.

Effects of androgen and oestrogen on IGF pathways controlling phallus growth

“…However, MAFB subsequently increased in male phalluses and became higher than that in female phalluses by day 90 pp. This was not expected since the expression of Mafb is upregulated in male phalluses in mice, but these were sampled before E18.5, well before the male phallus growth and elongation takes place , Matsushita et al 2015. Interestingly, from our previous studies in the tammar, SHH was significantly higher in female phalluses between day 30 and day 40 pp but lower in female phalluses between day 50 to day 60 pp (Chew et al 2014).…”

“…It is possible that MAFB may be a downstream target of SHH signalling under the negative regulation of androgen. In addition, Mafb expression is also controlled by β-catenin, the transcription factor of Wingless-Type MMTV Integration Site Family, Member (WNT)/β-catenin pathway (Matsushita et al 2015). Figure 4 qPCR analysis on the expression of FGF10, FGFR2IIIb, EFNB2, MAFB and DLX5 during postnatal phallus development.…”

“…If any part of the pathway is missing, severe hypospadias and urorectal malformations occur (Dravis et al 2004, Yucel et al 2007). V-Maf Avian Musculoaponeurotic Fibrosarcoma Oncogene Homologue B (Mafb), an androgen-dependent gene, is predominantly expressed in mesenchymal cells of male phalluses , Matsushita et al 2015. In mice, its expression is upregulated in female GT mesenchyme after exogenous androgen treatment, but is downregulated in male GT mesenchyme of androgen receptor (Ar) knockouts (KO) .…”

Developmental mutant mouse models for external genitalia formation

“…Search for such regulatory genes is under progress. As a candidate factor for androgen and the mediators, canonical Wnt signal is also necessary for early-staged GT formation 28,29,59,60 and also for androgen-induced gene expres- androgen receptor (AR). [63][64][65] Among androgen target genes, epithelial regulatory gene p63 gene has been also identified and a unique gene regulatory element has been revealed.…”

“…63 Recently, presence of androgen responsive enhancer and ARE have been shown as also regulating androgen inducible urethra formation in the case of MafB gene. 60 Acquisition of androgen dependency is a prominent character of external genitalia formation as a process for masculinization. Integrative approaches utilizing conditional gene modification system and identification of androgen-target genes will reveal further progresses in the near future.…”