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
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.