title: BRCA2 deficiency in mice leads to meiotic impairment and infertility.
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.
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute at Frederick, 1050 Boyles Street, Frederick, MD 21702, USA. ssharan@mail.ncifcrf.gov
authors.forename: Shyam K
authors.initials: SK
authors.lastname: Sharan
authors.forename: April
authors.initials: A
authors.lastname: Pyle
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Coppola
authors.forename: Janice
authors.initials: J
authors.lastname: Babus
authors.forename: Srividya
authors.initials: S
authors.lastname: Swaminathan
authors.forename: Jamie
authors.initials: J
authors.lastname: Benedict
authors.forename: Deborah
authors.initials: D
authors.lastname: Swing
authors.forename: Betty K
authors.initials: BK
authors.lastname: Martin
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
authors.forename: Janice P
authors.initials: JP
authors.lastname: Evans
authors.forename: Jodi A
authors.initials: JA
authors.lastname: Flaws
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Handel
mesh_terms: D000818:Animals; D024682:BRCA2 Protein / Q000172:deficiency / Q000235:genetics*; D005314:Embryonic and Fetal Development / Q000235:genetics*; D005260:Female; D005313:Fetal Death / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D024522:Genes, BRCA2; D006801:Humans; D017403:In Situ Hybridization; D007248:Infertility, Male / Q000235:genetics; D008297:Male; D008540:Meiosis / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009865:Oocytes / Q000166:cytology / Q000502:physiology; D016133:Polymerase Chain Reaction; D013090:Spermatocytes / Q000166:cytology / Q000502:physiology
chemical_list: D024682:BRCA2 Protein