The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse.
Mutations of the BRCA1 gone in humans are associated with predisposition to breast and ovarian cancers. We show here that Brca1+/- mice are normal and fertile and lack tumors by age eleven months. Homozygous Brca1(5-6) mutant mice die before day 7.5 of embryogenesis. Mutant embryos are poorly developed, with no evidence of mesoderm formation. The extraembryonic region is abnormal, but aggregation with wild-type tetraploid embryos does not rescue the lethality. In vivo, mutant embryos do not exhibit increased apoptosis but show reduced cell proliferation accompanied by decreased expression of cyclin E and mdm-2, a regulator of p53 activity. The expression of cyclin-dependent kinase inhibitor p21 is dramatically increased in the mutant embryos. Buttressing these in vivo observations is the fact that mutant blastocyst growth is grossly impaired in vitro. Thus, the death of Brca1(5-6) mutant embryos prior to gastrulation may be due to a failure of the proliferative burst required for the development of the different germ layers.
Hakem
R
R
Amgen Institute, Toronto, Ontario, Canada.
de la Pompa
J L
JL
Sirard
C
C
Mo
R
R
Woo
M
M
Hakem
A
A
Wakeham
A
A
Potter
J
J
Reitmair
A
A
Billia
F
F
Firpo
E
E
Hui
C C
CC
Roberts
J
J
Rossant
J
J
Mak
T W
TW
D017398:Alternative Splicing / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D019313:BRCA1 Protein; D001483:Base Sequence; D002455:Cell Division / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000502:physiology; D005804:Genes, Lethal / Q000502:physiology; D016147:Genes, Tumor Suppressor / Q000235:genetics; D006580:Genetic Carrier Screening; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000235:genetics*; D008648:Mesoderm / Q000166:cytology / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2; D014157:Transcription Factors / Q000235:genetics*; D014327:Trophoblasts / Q000166:cytology / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D019313:BRCA1 Protein; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2