PARENT SESSION
PLATFORM SESSION 12: GENETICS AND GENOMICS OF THE REGULATION AND EXECUTION OF SPERMATOGENESIS
Chair: McClean, Derek¹, ¹
Co-chair: Hung-Chang Yao, Humphrey¹, ¹
Harborside A
2:00 PM-4:00 PM

(235) THE ROLE OF THE BREAST CANCER-ASSOCIATED GENE 1 IN SPERMATOGENESIS.

Xu, Xiaoling¹, Furth, Priscilla¹, ¹ Department of Physiology, University Maryland Medical School., Baltimore, MD

ABSTRACT- Germline mutations of the breast cancer-associated gene 1 (BRCA1) predispose women to breast and ovarian cancers. In mouse, analysis of Brca1 mutant embryos revealed that Brca1 plays essential roles in cell growth, genome integrity and cell cycle regulation. However the mechanisms underlying these defects remain to be illustrated. To further study the role of BRCA1 in maintaining genetic stability, we study meiosis in mutant mice, which are homozygous for a targeted deletion of Brca1 exon 11 and heterozygous for a p53-null mutation (Brca1D11/D11p53+/-). The Brca1D11/D11p53+/- mice can survive to adulthood; however, all males are infertile and females exhibited decreased fertility. We show that the mutant testes contain spermatogonia and early stage of primary spermatocytes, however do not have spermatid and spermatozoon. Chromosome analyses indicate that mutant testes contain normal percentages of spermatocytes at pachytene stage; however, almost all of them can not develop into diplotene stage, suggesting that the block of first wave spermatogenesis occurs right after homologous chromosome pairing at meiosis I. We further demonstrate that mutant homologous chromosomes can pair but fail to form crossover, an event that is essential for the information exchange between homologous chromosomes. To distinguish whether the block is caused by decreased cell proliferation or increased cell death, we performed BrdU labeling and TUNEL assay. Our data reveal no significant difference in premeiotic spermatogonical proliferation; however significantly increased apoptosis is observed in testes of postnatal day 16 and older mice. Consistently, our RNA microarray reveal expression changes of many genes involved in the p53 dependent and/or independent apoptotic pathways. Thus, our study reveals an essential role of Brca1 in regulating genetic exchange of homologous chromosomes during spermatogenesis. The loss of Brca1, therefore, leads to genome instability and triggers the activation of both the p53 dependent and independent apoptotic pathways, resulting in the failure of spermatogenesis.

KEY WORDS: Brca1, Spermatogenesis, Diplotene, Apoptosis