Placental and embryonic growth restriction in mice with reduced function epidermal growth factor receptor alleles.

Embryos lacking an epidermal growth factor receptor (EGFR) exhibit strain-specific defects in placental development that can result in mid-gestational embryonic lethality. To determine the level of EGFR signaling required for normal placental development, we characterized congenic strains homozygous for the hypomorphic Egfr(wa2) allele or heterozygous for the antimorphic Egfr(Wa5) allele. Egfr(wa2) homozygous embryos and placentas exhibit strain-dependent growth restriction at 15.5 days post-coitus while Egfr(Wa5) heterozygous placentas are only slightly reduced in size with no effect on embryonic growth. Egfr(wa2) homozygous placentas have a reduced spongiotrophoblast layer in some strains, while spongiotrophoblasts and glycogen cells are almost completely absent in others. Our results demonstrate that more EGFR signaling occurs in Egfr(Wa5) heterozygotes than in Egfr(wa2) homozygotes and suggest that Egfr(wa2) homozygous embryos model EGFR-mediated intrauterine growth restriction in humans. We also consistently observed differences between strains in wild-type placenta and embryo size as well as in the cellular composition and expression of trophoblast cell subtype markers and propose that differential expression in the placenta of Glut3, a glucose transporter essential for normal embryonic growth, may contribute to strain-dependent differences in intrauterine growth restriction caused by reduced EGFR activity.