International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


KE Strunk
University of North Carolina-Chapel Hill

Threadgill DW
University of North Carolina-Chapel Hill

The genetic background-dependent phenotype of a targeted mutation in the epidermal growth factor receptor (Egfrtm1Mag) is the prototypical example of how differences in genetic background can have profound phenotypic consequences. Homozygous Egfrtm1mag null mutants exhibit peri-implantation to post-natal lethality, depending on the genetic background. On a 129S6 background Egfr homozygous null embryos die at embryonic day 11.5 due to placental defects. The placentae show a decreased size compared to those from control littermates, with a reduced spongiotrophoblast layer and disorganization of the labyrinthine layer. On an outbred Swiss-derived CD-1 background homozygous null pups also exhibit a reduced spongiotrophoblast layer, but with a partial rescue of the labyrinthine layer. Initial genome scans did not detect any statistically significant genetic modifiers between the CD-1 and 129S6 backgrounds. In order to survey and partition the genetic variability segregating in mouse strains, we derived a series of congenic lines using strains of diverse origin and tested 10 inbred Swiss-derived strains using F2 intercrosses. These genetic analyses revealed the existence of extensive and diverse genetic background modifiers for the Egfr null phenotype. Concurrently, we have investigated the mechanism by which these modifiers function to modify the Egfr-deficient phenotype. Gene-expression profiling and detailed molecular and histological analyses suggest that Egfr is required for trophoblast cells to transit normally through the cell cycle during mid-gestation. Genetic crosses have been established to directly test the role of Egfr in cell-cycle progression during placenta development. The collective analysis of this prototypical example of genetic background modifiers will be presented.

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