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

Andrology Laboratory (P.L., M.R., J.S., K.J.M., M.J., D.J.H., C.M.A.), ANZAC Research Institute, University of Sydney, Concord Hospital, Concord, New South Wales 2139, Australia; and Department of Medicine (J.D.Z.), University of Melbourne, Austin Health, Heidelberg 3084, Victoria, Australia

Address all correspondence and requests for reprints to: Charles M. Allan, ANZAC Research Institute, Concord Hospital, Sydney, New South Wales 2139, Australia. E-mail: charles{at}med.usyd.edu.au.

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 AR^ZF2 lines designated Abp.SCAR^ZF2 and AMH.SCAR^ZF2, respectively. Both SCAR^ZF2 lines produced infertile males exhibiting spermatogenic arrest, despite normal SC numbers and immunolocalized SC nuclear AR. Adult homozygous TgCre^(+/+) SCAR^ZF2 or double-TgCre^(+/–) Abp/AMH.SCAR^ZF2 males displayed equivalent small testes 30% of normal size, representing maximal Cre-loxP-disruption of Sertoli AR function. Hemizygous TgCre^(+/–) vs. homozygous TgCre^(+/+) Abp.SCAR^ZF2 testes were larger (47% normal size) with more postmeiotic development, indicating dose-dependent Cre-mediated disruption of SC-specific AR-DBD activity. SCAR^ZF2 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 SCAR^ZF2 vs. 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^(+/+) SCAR^ZF2 testes, revealing differential temporal control for distinct AR-regulated transcripts. Androgen-repressed Ngfr was not up-regulated in SCAR^ZF2 testes, suggesting maintenance of a nonclassical mechanism independent of AR-DBD. Thus, our unique SCAR^ZF2 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.