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First published online 3 December 2003
doi: 10.1242/dev.00888
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1 Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer
Institute at Frederick, 1050 Boyles Street, Frederick, MD 21702, USA
2 Department of Biochemistry and Cellular and Molecular Biology, University of
Tennessee, Knoxville, TN 37996, USA
3 Department of Epidemiology and Preventive Medicine, School of Medicine,
University of Maryland, Baltimore, MD 21201, USA
4 Department of Biochemistry and Molecular Biology, Division of Reproductive
Biology, Johns Hopkins University, Bloomberg School of Public Health,
Baltimore, MD 21205, USA
* Author for correspondence (e-mail: ssharan{at}mail.ncifcrf.gov)
Accepted 29 September 2003
The role of Brca2 in gametogenesis has been obscure because of embryonic lethality of the knockout mice. We generated Brca2-null mice carrying a human BAC with the BRCA2 gene. This construct rescues embryonic lethality and the mice develop normally. However, there is poor expression of the transgene in the gonads and the mice are infertile, allowing examination of the function of BRCA2 in gametogenesis. BRCA2-deficient spermatocytes fail to progress beyond the early prophase I stage of meiosis. Observations on localization of recombination-related and spermatogenic-related proteins suggest that the spermatocytes undergo early steps of recombination (DNA double strand break formation), but fail to complete recombination or initiate spermiogenic development. In contrast to the early meiotic prophase arrest of spermatocytes, some mutant oocytes can progress through meiotic prophase I, albeit with a high frequency of nuclear abnormalities, and can be fertilized and produce embryos. Nonetheless, there is marked depletion of germ cells in adult females. These studies provide evidence for key roles of the BRCA2 protein in mammalian gametogenesis and meiotic success.
Key words: BRCA2, Spermatogenesis, Oogenesis, Meiosis, DNA repair
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