Retinoic acid receptor signaling is necessary in steroidogenic cells for normal spermatogenesis and epididymal function

Abstract

Spermatogenesis in mammals is a very complex, highly organized process, regulated in part by testosterone and retinoic acid (RA). There is a significant amount known about how RA and testosterone signaling pathways independently regulate this process, but there is almost no information regarding whether these two signaling pathways directly interact and whether RA is critical for steroidogenic cell function. This study utilized a transgenic mouse line that expresses a dominant negative form of RA receptor α (RAR−DN) and the steroidogenic cell−specific Cre mouse line, Cyp17iCre, to generate male mice with steroidogenic cells unable to perform RA signaling. Testes of mutant mice displayed increased apoptosis of pachytene spermatocytes, increased number of macrophages in the interstitium, and missing advanced germ cells. Additionally, blocking RA signaling in Leydig cells resulted in increased permeability of the blood-testis barrier, decreased levels of the steroidogenic enzyme cytochrome P450 17a1, and decreased testosterone levels. Surprisingly, the epididymides of the mutant mice also displayed an abnormal phenotype. This study demonstrates that RA signaling is required in steroidogenic cells for their normal function and, thus, for male fertility.