Altered Trophoblast Proliferation is Insufficient to Account for Placental Dysfunction in Egfr Null Embryos

Abstract

Homozygosity for the Egfr(tm1Mag) null allele in mice leads to genetic background dependent placental abnormalities and embryonic lethality. Molecular mechanisms or genetic modifiers that differentiate strains with surviving versus non-surviving Egfr nullizygous embryos have yet to be identified. Egfr transcripts in wildtype placenta were quantified by ribonuclease protection assay (RPA) and the lowest level of Egfr mRNA expression was found to coincide with Egfr(tm1Mag) homozygous lethality. Immunohistochemical analysis of ERBB family receptors, ERBB2, ERBB3, and ERBB4, showed similar expression between Egfr wildtype and null placentas indicating that Egfr null trophoblast do not up-regulate these receptors to compensate for EGFR deficiency. Significantly fewer numbers of bromodeoxyuridine (BrdU) positive trophoblast were observed in Egfr nullizygous placentas and Cdc25a and Myc, genes associated with proliferation, were significantly down-regulated in null placentas. However, strains with both mild and severe placental phenotypes exhibit reduced proliferation suggesting that this defect alone does not account for strain-specific embryonic lethality. Consistent with this hypothesis, intercrosses generating mice null for cell cycle checkpoint genes (Trp53, Rb1, Cdkn1a, Cdkn1b or Cdkn2c) in combination with Egfr deficiency did not increase survival of Egfr nullizygous embryos. Since complete development of the spongiotrophoblast compartment is not required for survival of Egfr nullizygous embryos, reduction of this layer that is commonly observed in Egfr nullizygous placentas likely accounts for the decrease in proliferation.

Genes and signals regulating murine trophoblast cell development

“…Furthermore, studies by Dackor et al (2007, 2009a,2009b) highlighted the importance of EGFR, which is a member of the ERBB family of receptor tyrosine kinases, in placental development. In mice that are Egfr(tm1Mag) nullizygous, placentas have fewer proliferative trophoblasts than wild-type and exhibit strain-specific defects in the spongiotrophoblast and labyrinth layers (Dackor et al, 2007, 2009a).…”

RNA Interference Against Hepatic Epidermal Growth Factor Receptor Has Suppressive Effects on Liver Regeneration in Rats

“…The resulting phenotype was dependent on strain and genetic background with abnormalities in various organs like liver, brain, and kidneys. [22][23][24] There have been two recent studies that addressed the role of EGFR in liver regeneration after a PHx. In one study, a monoclonal antibody (mAB) targeting EGFR was used to inhibit EGFR, 25 and its impact on liver regeneration was studied.…”

Epidermal growth factor, from gene organization to bedside

“…EGFR expression has been detected in the apical blastomere membrane of the 4-cell stage mouse embryo [62,76]. In EGFR null mice, placentas have fewer proliferative trophoblasts than wild-type and exhibit strain-specific defects in the spongiotrophoblast and labyrinth layers that can result in mid-gestational embryonic lethality [77–79]. Moreover, increasing the levels of EGFR signaling by using hypermorphic EGFR (Dsk5) allele results in larger placental size with a more prominent spongiotrophoblast layer and increased expression of glycogen cell-specific genes [80].…”