Testis

Androgen Regulation of Stage-Dependent Cyclin D2 Expression in Sertoli Cells Suggests a Role in Modulating Androgen Action on Spermatogenesis

Abstract
Regulation of spermatogenesis involves stage-dependent androgen action on Sertoli cells, but the pathways involved are unclear. We assessed if cyclin D2 could play a role. In rats, Sertoli cell nuclear, stage-dependent immunoexpression of cyclin D2 switched on after d10, persisted through d35 but disappeared by adulthood. However, EDS-induced testosterone (TE) withdrawal in adult rats for 6d induced stage-dependent cyclin D2 immunoexpression in Sertoli cells, with highest expression at stages IX-XII and non-detectable at stages VI-VIII (opposite that for androgen receptor (AR) immunoexpression). In EDS-treated rats, a single injection of TE, but not of estrogen, reversed this change in 4h and TE administration from the time of EDS-treatment prevented expression of cyclin D2 in Sertoli cells. The EDS-induced changes in cyclin D2 immunoexpression were matched by changes in expression of Ccnd2 (cyclin D2) mRNA in isolated stage-dissected tubules. Treatment of adult rats with flutamide induced stage-dependent cyclin D2 immunoexpression in Sertoli cells within 18h, and confocal microscopy revealed that immunoexpression of AR and cyclin D2 were mutually exclusive within individual seminiferous tubules in these animals. Sertoli cell-selective ablation of the AR in mice using Cre/loxP technology also resulted in stage-dependent Sertoli cell cyclin D2 immunoexpression. Downstream from cyclin D2 action is the retinoblastoma 1 (RB1), a tumor suppressor protein, immunoexpression of which paralleled stage-dependent AR expression in Sertoli cells; RB1 stage-specificity disappeared after EDS treatment. These results point to a non-cell cycle role for cyclin D2 and RB1 in mature Sertoli cells in the stage-dependent mechanisms regulated by AR expression and androgen action.

Key words: Sertoli cells • Spermatogenesis • Testosterone

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