Testis

BARD1 Expression During Spermatogenesis Is Associated with Apoptosis and Hormonally Regulated

Abstract
The BRCA1-binding RING finger domain protein BARD1 may act conjointly with BRCA1 in DNA repair and in ubiquitination, but it may also induce apoptosis in a BRCA1-independent manner. In this study we have investigated BARD1 expression during spermatogenesis. In contrast to BRCA1, which is expressed only in meiotic spermatocytes and early round spermatids, BARD1 is expressed during all stages of spermatogenesis. However, while spermatogonia expressed full length BARD1 mRNA, later stages of spermatocyte precursors express predominantly a novel, shorter splice form BARD1. BARD1 lacks the BRCA1-interacting RING finger, but maintains its proapoptotic activity. Consistently, BRCA1 can counteract the proapoptotic activity of full length BARD1, but not of BARD1. Several lines of evidence suggest that BARD1 is involved in pro-apoptotic signaling in testis: i) both BARD1 isoforms are mostly found in cells that stain positive for TUNEL, Bax, and activated caspase 3; ii) BARD1, capable of inducing apoptosis even in the presence of BRCA1, is specifically expressed in BRCA1-positive later stages of spermatogenesis; iii) anti-apoptotic hormonal stimulation leads to BARD1 downregulation, and iv) BARD1 expression is associated with human pathologies causing sterility due to increased germ cells death. Our data suggest that full length BARD1 might be involved in apoptotic control in spermatogonia and primary spermatocytes, while a switch to the BRCA1-independent BARD1 might be necessary to induce apoptosis in BRCA1-expressing meiotic spermatocytes and early round spermatids.

Key words: Apoptosis • Meiosis • Spermatogenesis • Steroid hormones

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