Gene replacement with the human BRCA1 locus: tissue specific expression and rescue of embryonic lethality in mice

Citation
Tf. Lane et al., Gene replacement with the human BRCA1 locus: tissue specific expression and rescue of embryonic lethality in mice, ONCOGENE, 19(36), 2000, pp. 4085-4090
Citations number
35
Categorie Soggetti
Onconogenesis & Cancer Research
Journal title
ONCOGENE
ISSN journal
09509232 → ACNP
Volume
19
Issue
36
Year of publication
2000
Pages
4085 - 4090
Database
ISI
SICI code
0950-9232(20000824)19:36<4085:GRWTHB>2.0.ZU;2-I
Abstract
We have generated transgenic mice that harbor a 140 kb genomic fragment of the human BRCA1 locus (TgN.BRCA1(GEN)). We find that the transgene directs appropriate expression of human BRCA1 transcripts in multiple mouse tissues , and that human BRCA1 protein is expressed and stabilized following exposu re to DIVA damage, Such mice are completely normal, with no overt signs of BRCA1 toxicity commonly observed when BRCA1 is expressed from heterologous promoters. Most importantly, however, the transgene rescues the otherwise l ethal phenotype associated with the targeted hypomorphic allele (Brca1(Delt a exIISA)). Brca1(-/-); TgN.BRCA1(GEN) bigenic animals develop normally and can be maintained as a distinct line. These results show that a 140 kb fra gment of chromosome 17 contains all elements necessary for the correct expr ession, localization, and function of the BRCA1 protein, Further, the model provides evidence that function and regulation of the human BRCA1 gene can be studied and manipulated in a genetically tractable mammalian system.