Altered trophoblast proliferation is insufficient to account for placental dysfunction in Egfr null embryos.
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.
Dackor
J
J
Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
Strunk
K E
KE
Wehmeyer
M M
MM
Threadgill
D W
DW
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D049109:Cell Proliferation; D003433:Crosses, Genetic; D020964:Embryo Loss / Q000235:genetics; D066246:ErbB Receptors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005260:Female; D018816:Genes, cdc; D006720:Homozygote; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010920:Placenta / Q000473:pathology / Q000503:physiopathology*; D010922:Placenta Diseases / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D015398:Signal Transduction / Q000235:genetics; D013045:Species Specificity; D014158:Transcription, Genetic; D014327:Trophoblasts / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation