Decidual angiogenesis and placental orientation are altered in mice heterozygous for a dominant loss-of-function Gja1 (connexin43) mutation.
Connexin43 (CX43), encoded by Gja1 in the mouse, is highly expressed in decidual cells and is known to be important for the transformation of stromal cells into the compact decidua and for neoangiogenesis. Here we investigated if the dominant Gja1(Jrt) mutation encoding CX43(G60S) in mice, which results in a phenotype resembling oculodentodigital dysplasia in humans, has an impact on decidualization, angiogenesis, and implantation. We found a reduced mean weight of fetuses at Gestational Day 17.5 in dams carrying this mutation, with the growth deficiency being independent of fetal genotype. Although the mutant implantation sites exhibited a reduction in CX43 protein, with most immunoreactivity being cytoplasmic, the decidua was morphologically intact at Embryonic Days 5.5 to 7.5. However, the mutation resulted in enhanced and irregular angiogenesis and an increased level of expression of the angiogenic factor-encoding genes Vegfa, Flt1, Kdr, and Fgf2 as well as the prolactin-related gene Prl6a. Moreover, immunolocalization of VEGFA, FLT1, and KDR revealed a homogeneous distribution pattern in the mesometrial as well as antimesometrial decidua of the mutants. Most obviously, uterine NK cells are drastically diminished in the mesometrial decidua of the mutant mice. Invasion of ectoplacental cone cells was disoriented, and placentation was established more laterally in the implantation chambers. It was concluded that the CX43(G60S) mutant impairs control of decidual angiogenesis, leading to dysmorphic placentation and fetal growth restriction. This phenomenon could contribute to the reduced fetal weights and viability of pups born of Gja1(Jrt)/+ dams.
Department of Molecular Biology, University Clinics Essen, University of Duisburg-Essen, Essen, Germany.
Elke
E
Winterhager
Alexandra
A
Gellhaus
Sandra M
SM
Blois
Lesley A
LA
Hill
Kevin J
KJ
Barr
Gerald M
GM
Kidder
D000818:Animals; D000831:Animals, Newborn; D016764:Cell Polarity / Q000235:genetics; D018389:Codon, Nonsense; D018031:Connexin 43 / Q000235:genetics*; D003656:Decidua / Q000098:blood supply*; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics; D005799:Genes, Dominant; D006579:Heterozygote; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000235:genetics*; D010920:Placenta / Q000166:cytology* / Q000502:physiology*; D021041:Placental Circulation / Q000235:genetics; D010929:Placentation / Q000235:genetics; D011247:Pregnancy
D018389:Codon, Nonsense; D018031:Connexin 43; C543076:GJA1 protein, mouse
CX43; Gja1 mutation; ODDD; angiogenesis; decidua; natural killer cells