TRANSGENES ENCODING BOTH TYPE-I AND TYPE-IV C-ABL PROTEINS RESCUE THELETHALITY OF C-ABL MUTANT MICE

Mice carrying homozygous mutations in the c-abl gene (abl(ml) or abl(2 )) exhibit severe, though variable phenotypes, including a high rate o f postnatal mortality, runting, morphological abnormalities, a suscept ibility to infections, and selected immune system defects, To further determine the role of the c-Abl protein in vivo, we have generated thr ee lines of mice expressing c-abl transgenes, These minigenes encode t he two major forms of the c-abl gene product (c-Abl types I and IV) an d a kinase defective type IV c-Abl. The transgenic lines, in Abl-posit ive genetic backgrounds, were phenotypically almost indistinguishable from their non-transgene littermates and expressed the c-ab! transgene in a variety of tissues at levels comparable to that of the endogenou s c-abl gene. When the transgenes were introduced into a mutant c-abl strain by mating, the mutant c-abl phenotype was almost completely res cued by either of the c-abl type I or type IV transgenes, but not by t he kinase-defective transgene, These findings suggest that either of t he two alternatively spliced c-abl gene products can provide the in vi vo functions of c-Abl, and that these functions are dependent on kinas e activity.