International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)


I21. Molecular and Genetic Analysis of the Epidermal Growth Factor Receptor

Karen E. Strunk, Vicky Amann, David W. Threadgill
Department of Genetics, University of North Carolina, Chapel Hill, NC USA 27599-7264

The epidermal growth factor receptor (Egfr) is the prototypical member of a family of related tyrosine kinase receptors that includes Erbb2, Erbb3 and Erbb4. Egfr, a widely-expressed gene spanning greater than 100 kb, encodes two primary, alternatively-spiced transcripts that produce 170 and 95kDa proteins.

Homozygous Egfr null mutants exhibit peri-implantation to post-natal lethality, depending on the genetic background. On a 129/SvEvTAC background Egfr homozygous null embryos die at embryoinic day (e) 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. However, on an outbred CD-1 background homozygous null pups can survive as long as postnatal day (P) 18, but are severely runted and show progressive wasting. Surprisingly, the placentae still exhibit a reduced spongiotrophoblast layer, but there is partial rescue of the disorganized labyrinthine layer. Therefore, loss of Egfr function during development appears to impact the normal growth and differentiation of the placenta.

To address the strain dependant variability, a scan for genetic modifiers was performed using the outbred CD-1 background. No statistically significant loci were identified in a large backcross mapping panel. In order to partition the genetic variability potentially segregating within the outbred Swiss-derived CD-1 population, we tested 11 inbred Swiss-derived strains to determine the viability of Egfr null mutants. The strains tested include ALR/LtJ, ALS/LtJ, NON/LtJ, NOD/LtJ, ICR/HaRos, ICR/Bc, SJL/J, SWR/J, FVB/NJ, APN, and APS. We reasoned that different inbred strains derived from the same Swiss population as the outbred CD-1 mice would have captured different sets of modifier alleles. As predicted, a significant variation in the penetrance of Egfr null viability was observed in the various inbred strains. Furthermore, parental origin effects, possibly imprinted modifiers, have been detected that modify Egfr viability. The genetic modifiers are being mapped in crosses with these inbred strains.


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