SUN-719 The Impact of FOXA3 on Testicular Steroidogenesis

The Forkhead box(Fox) transcription factors are evolutionarily conserved in organisms and regulate diverse biological processes during development as well as adult life. Among the Fox family, FoxA subfamily members Foxa1-3 have been termed `pioneer’ transcription factors as they bind both nucleosome-bound and nucleosome-free DNA targets with the same recognition site. Foxa3 is the only member of FoxA subfamily that is expressed in both male and female gonads. In the testis, Foxa3 is expressed in spermatids and interstitial Leydig cells. We focused our study to elucidate the role of FOXA3 in Leydig cells and its impact on testicular steroidogenesis. Expression of FOXA3 dramatically decreased in mouse Leydig cells during testicular development. In addition, the time-dependent expression of FOXA3 showed an opposite pattern to that of steroidogenic genes in cAMP-induced primary Leydig cells. Meanwhile, Nur77 is among the prime regulators of steroidogenesis in the testicular Leydig cells. Overexpression of FOXA3 in MA-10 cells (mouse Leydig tumor cell line) repressed the cAMP-induced Nur77 promoter activity, which further resulted in the reduced activity of Nur77-target steroidogenic gene promoters (StAR, CYP17A1and 3β-HSD). Similar to above results, the expression of Nur77 and its target genes,StAR, 3β-HSD and CYP11A1, were repressed by adenovirus-mediated overexpression of FOXA3 in mouse primary Leydig cells, although the expression of CYP17A1, another steroidogenic gene, was differentially affected. These results suggest that FOXA3 locally regulates the expression of steroidogenic genes through Nur77 during testicular development.