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This version published online on July 2, 2009
Endocrinology, doi:10.1210/en.2009-0416
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*Compound via MeSH
*Substance via MeSH

Submitted on April 3, 2009
Accepted on June 22, 2009

Sertoli cell androgen receptor DNA binding domain is essential for the completion of spermatogenesis

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

Andrology Laboratory, ANZAC Research Institute, (P.L., M.R., J.S., K.J.M., M.J., D.J.H., C.M.A.), University of Sydney, Concord Hospital, Concord NSW 2139, NSW Australia; Dept of Medicine (J.D.Z.), University of Melbourne, Austin Health, Heidelberg, VIC Australia

* To whom correspondence should be addressed. 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{Delta}ZF2 lines designated Abp.SCAR{Delta}ZF2 and AMH.SCAR{Delta}ZF2 respectively. Both SCAR{Delta}ZF2 lines produced infertile males exhibiting spermatogenic arrest, despite normal SC numbers and immunolocalized SC nuclear AR. Adult homozygous TgCre(+/+) SCAR{Delta}ZF2 or double TgCre(+/-) Abp/AMH.SCAR{Delta}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{Delta}ZF2 testes were larger (47% normal size) with more post-meiotic development, indicating dose-dependent Cre-mediated disruption of SC-specific AR-DBD activity. SCAR{Delta}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{Delta}ZF2 vs. control testes, demonstrating SC-specific AR-DBD function as early as postnatal day 5. However, Rhox5 expression declined dose-dependently, whereas Spinlw1 expression increased, in adult TgCre(+/-) and TgCre(+/+) SCAR{Delta}ZF2 testes, revealing differential temporal control for distinct AR-regulated transcripts. Androgen-repressed Ngfr was not upregulated in SCAR{Delta}ZF2 testes, suggesting maintenance of a non-classical mechanism independent of AR-DBD. Thus, our unique SCAR{Delta}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 post-meiotic spermatogenesis. Non-genomic or AR-DBD-independent pathways appear secondary, or play no major independent role in SC function.
Key words: Androgen receptor • genomic action • transgenic mouse • Sertoli cell • spermatogenesis






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