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Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
Published on: August 12, 2015
BRCA2 deficiency in mice leads to meiotic impairment and infertility
Shyam K Sharan1, April Pyle, Vincenzo Coppola
1Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute at Frederick, 1050 Boyles Street, Frederick, MD 21702, USA. ssharan@mail.ncifcrf.gov
Abstract:
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.
Insights
The BRCA2 gene is crucial for successful gametogenesis in mice. BRCA2 deficiency in male mice halts meiosis, while female mice show germ cell depletion and fertility issues.
Area of Science:
- Genetics
- Reproductive Biology
- Molecular Biology
Background:
- The function of Breast Cancer gene 2 (Brca2) in gametogenesis remained unclear due to embryonic lethality in knockout mice.
- A human bacterial artificial chromosome (BAC) carrying the BRCA2 gene was used to overcome this lethality.
Purpose of the Study:
- To investigate the role of BRCA2 in mammalian gametogenesis and meiotic progression.
- To analyze the impact of BRCA2 deficiency on spermatogenesis and oogenesis.
Main Methods:
- Generation of Brca2-null mice with a human BRCA2 transgene to rescue embryonic lethality.
- Assessment of transgene expression in gonads and evaluation of fertility.
- Microscopic analysis of meiotic progression, protein localization, and germ cell survival in mutant mice.
Main Results:
- Transgene expression was poor in gonads, leading to infertility in rescued mice.
- BRCA2-deficient spermatocytes arrested at early prophase I of meiosis, failing to complete recombination and spermiogenesis.
- Mutant oocytes showed meiotic progression but with nuclear abnormalities; adult females exhibited germ cell depletion.
Conclusions:
- BRCA2 plays a critical role in mammalian gametogenesis, particularly in ensuring meiotic success.
- The protein is essential for the completion of meiosis in spermatocytes and for maintaining germ cell populations in females.
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