Androgen/Wnt/β‐catenin signal axis augments cell proliferation of the mouse erectile tissue, corpus cavernosum

Abstract

The murine penile erectile tissues including corpus cavernosum (CC) are composed of blood vessels, smooth muscle, and connective tissue, showing marked sexual differences. It has been known that the androgens are required for sexually dimorphic organogenesis. It is however unknown about the features of androgen signaling during mouse CC development. It is also unclear how androgen-driven downstream factors are involved such processes. In the current study, we analyzed the onset of sexually dimorphic CC formation based on histological analyses, the dynamics of androgen receptor (AR) expression, and regulation of cell proliferation. Of note, we identified Dickkopf-related protein 2 (Dkk2), an inhibitor of β-catenin signaling, was predominantly expressed in female CC compared with male. Furthermore, administration of androgens resulted in activation of β-catenin signaling. We have found the Sox9 gene, one of the essential markers for chondrocyte, was specifically expressed in the developing CC. Hence, we utilized CC-specific, Sox9 CreERT2 , β-catenin conditional mutant mice. Such mutant mice showed defective cell proliferation. Furthermore, introduction of activated form of β-catenin mutation (gain of function mutation for Wnt/β-catenin signaling) in CC induced augmented cell proliferation. Altogether, we revealed androgen-Wnt/β-catenin signal dependent cell proliferation was essential for sexually dimorphic CC formation. These findings open new avenues for understanding developmental mechanisms of androgen-dependent cell proliferation during sexual differentiation.

Possible testosterone redundancy for 5α-dihydrotestosterone in the masculinization of mouse external genitalia

“…Sexual dimorphism of the size of the ExG becomes significant after birth and is induced via the androgen-Wnt/β-catenin signaling pathway [2]. It has been reported that Dkk2, which encodes an extracellular antagonist of canonical Wnt/β-catenin signaling, is expressed dominantly in female CC compared with the male CC at E16.5, leading to sexually dimorphic activation of β-catenin signaling [2]. A previous paper suggests that endothelial β-catenin signaling is a promoting factor in angiogenesis [31].…”

“…Although urethral tube formation has been well discussed, the development of the penile corpus cavernosum (hereafter referred to as the CC) is not understood. The CC is one of the major structures in ExG developing at the upper (dorsal) part of penis by androgen dependently [2]. It is known as the erectile tissue, which contains arterioles, sinusoidal spaces composed of endothelial cells, smooth muscle, and extracellular matrix (ECM) [3].…”

Emerging structural and pathological analyses on the erectile organ, corpus cavernous containing sinusoids

“…Therefore, regulation of Sox9 is also critical in early staged mesenchyme as well as late staged male type CC formation 76 . Previous studies suggested the androgenic CC formation with sinusoids occurs in pubertal period 76 . Altogether, investigation of Sox9 and Wnt signal should be further studied in both stages, that is, sex‐independent and ‐dependent CC formation and pathogenesis.…”

“…76 Therefore, regulation of Sox9 is also critical in early staged mesenchyme as well as late staged male type CC formation. 76 Previous studies suggested the androgenic CC formation with sinusoids occurs in pubertal period. 76 Altogether, investigation of Sox9 and Wnt signal should be further studied in both stages, that is, sex-independent and -dependent CC formation and pathogenesis.…”

“…75 Of note is the prominent embryonic Sox9 expression in both male and female presumptive CC inside the GT. 76,77 Furthermore, conditional knock out mouse studies for β-catenin, which is the critical canonical Wnt signaling regulator, identified potential role of Sox9 for regulating such embryonic sex-independent mesenchymal cell proliferation. 76 Therefore, regulation of Sox9 is also critical in early staged mesenchyme as well as late staged male type CC formation.…”