Use of an allelic series in mouse to study the role of epidermal growth factor receptor in placental development and pregnancy Public Deposited

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  • March 22, 2019
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  • Dackor, Jennifer Clore
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • Epidermal growth factor receptor (EGFR) is a member of the ERBB family of receptor tyrosine kinases that has been shown to play an important developmental and physiological role in many aspects of pregnancy. Using genetically engineered mice our lab and others have demonstrated that Egfrtm1Mag nullizygous placentas exhibit strain-specific defects ranging from mild reductions in spongiotrophoblasts to severe labyrinth dysmorphogenesis that results in mid-gestational embryonic lethality. Experiments included in this dissertation show that Egfrtm1Mag nullizygous placentas have reduced numbers of proliferating trophoblast. However, intercrosses with mice deficient for cell cycle checkpoint genes did not rescue Egfrtm1Mag embryo viability suggesting that reduced proliferation in the placenta is not a primary cause of embryonic lethality. We characterized an Egfr allelic series on several genetic backgrounds in mice to assess the effects of reduced as well as increased EGFR signaling on placental and embryonic growth. Congenic strains homozygous for the hypomorphic Egfrwa2 allele exhibited strain-dependent placental and embryonic growth restriction at 15.5 dpc while heterozygotes for the antimorphic EgfrWa5 allele had placentas were only slightly reduced in size with no effect on embryonic growth. At the histological level Egfrwa2 homozygous placentas had a reduced layer of spongiotrophoblast and in some strains spongiotrophoblasts and glycogen cells were almost completely absent. The placentas of embryos heterozygous or homozygous for the hypermorphic EgfrDsk5 allele were enlarged with a more prominent spongiotrophoblast layer and increased expression of glycogen cell-specific genes. There were no effects on growth of EgfrDsk5 embryos at 15.5 dpc. We also observed strain-specific sub-fertility in EgfrDsk5 heterozygous adult females that may be due deferred embryo implantation beyond the normal window of uterine receptivity. Our results demonstrate that EGFR plays a fundamental role in development of the placental spongiotrophoblast layer in mice and suggest that reduced proliferation in EGFR-deficient placentas primarily affects the spongiotrophoblast compartment. We have also shown that aberrant levels of EGFR signaling result in an extensive level of genetic background-dependent phenotypic variability and that EGFR expressed in the uterine stroma may function in preparation of the uterus for embryo implantation.
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  • Threadgill, David W.
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