BRCA2 deficiency in mice leads to meiotic impairment and infertility.
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.
Sharan
Shyam K
SK
Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute at Frederick, 1050 Boyles Street, Frederick, MD 21702, USA. ssharan@mail.ncifcrf.gov
Pyle
April
A
Coppola
Vincenzo
V
Babus
Janice
J
Swaminathan
Srividya
S
Benedict
Jamie
J
Swing
Deborah
D
Martin
Betty K
BK
Tessarollo
Lino
L
Evans
Janice P
JP
Flaws
Jodi A
JA
Handel
Mary Ann
MA
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
D024682:BRCA2 Protein