Portal de Periódicos da CAPES

Sertoli Cell Androgen Receptor DNA Binding Domain Is Essential for the Completion of Spermatogenesis

2009; Oxford University Press; Volume: 150; Issue: 10 Linguagem: Inglês

10.1210/en.2009-0416

1945-7170

Patrick Lim, Mathew Robson, Jenny Spaliviero, Kirsten J. McTavish, Mark Jimenez, Jeffrey D. Zajac, David J. Handelsman, Charles M. Allan,

Sexual Differentiation and Disorders

We examined the biological importance of Sertoli cell androgen receptor (AR) genomic interaction, using a Cre-loxP approach to selectively disrupt the AR DNA-binding domain (AR-DBD). Sertoli cell (SC)-specific transgenic Abpa or AMH promoters targeted Cre-mediated inframe excision of mouse Ar exon-3, encoding the AR-DBD second zinc-finger (ZF2), generating SC-specific mutant ARΔZF2 lines designated Abp.SCARΔZF2 and AMH.SCARΔZF2, respectively. Both SCARΔZF2 lines produced infertile males exhibiting spermatogenic arrest, despite normal SC numbers and immunolocalized SC nuclear AR. Adult homozygous TgCre(+/+) SCARΔZF2 or double-TgCre(+/−)Abp/AMH.SCARΔZF2 males displayed equivalent small testes 30% of normal size, representing maximal Cre-loxP-disruption of Sertoli AR function. Hemizygous TgCre(+/−)vs. homozygous TgCre(+/+)Abp.SCARΔZF2 testes were larger (47% normal size) with more postmeiotic development, indicating dose-dependent Cre-mediated disruption of SC-specific AR-DBD activity. SCARΔZF2 males exhibited adult Leydig cell hypertrophy but normal serum testosterone levels. Sertoli cell-specific Rhox5 and Spinlw1 transcription, regulated by divergent or classical androgen-response elements, respectively, were both decreased in postnatal SCARΔZF2vs. control testes, demonstrating SC-specific AR-DBD function as early as postnatal d 5. However, Rhox5 expression declined dose-dependently, whereas Spinlw1 expression increased, in adult TgCre(+/−) and TgCre(+/+) SCARΔZF2 testes, revealing differential temporal control for distinct AR-regulated transcripts. Androgen-repressed Ngfr was not up-regulated in SCARΔZF2 testes, suggesting maintenance of a nonclassical mechanism independent of AR-DBD. Thus, our unique SCARΔZF2 paradigm provided dose-dependent Cre-mediated disruption of testicular development and gene expression revealing that the AR-DBD is essential for SC function and postmeiotic spermatogenesis. Nongenomic or AR-DBD-independent pathways appear secondary or play no major independent role in SC function.