Connexin31-Deficiency in Mice Causes Transient Placental Dysmorphogenesis but Does Not Impair Hearing and Skin Differentiation

Abstract

Mutations in the human GJB3 gene that codes for Connexin31 (Cx31), a protein subunit of gap junction channels, have recently been reported to cause deafness and the skin disorder erythrokeratodermia variabilis. To study the function of this gene in mice, we generated animals with targeted replacement of the Cx31 gene (Gjb3) by a lacZ reporter gene. Although homozygous Cx31-deficient adult mice (Gjb3(-/-)) were found among the offspring of heterozygous Cx31-deficient parents (Gjb3(+/-)), 60% of the animals expected according to Mendelian inheritance were lost between ED 10.5 and 13.5. Placentas of Gjb3(-/-) embryos at ED 9.5 were smaller than controls as a result of severely reduced labyrinth and spongiotrophoblast size. From ED 10.5 onward, placentas of surviving Gjb3(-/-) embryos recovered progressively and reached normal size and morphology by ED 18.5. This corresponds to a time period in which another connexin isoform, Connexin43, is upregulated in spongiotrophoblast cells of Cx31-deficient and control placentas. No morphological or functional defects of skin or inner ear were observed in surviving adult Gjb3(-/-) mice. We conclude that Cx31 is essential for early placentation but can be compensated for by other connexins in the embryo proper and adult mouse.

Development and function of trophoblast giant cells in the rodent placenta

“…Mutants die by E10.5 with reduced spongiotrophoblast and TGC (Nadra et al, 2006, Wang et al, 2007 HIF bHLH/PAS transcription factors composed of HIFα and HIFβ/Arnt subunits Arnt -/-and Hif1α -/-Hif2α -/-die by E10.5 with TGC number increased, smaller ectoplacental cone and reduced spongiotrophoblast (Abbott and Buckalew, 2000, Adelman et al, 2000, Cowden Dahl et al, 2005 Cited 1 CBP/p300-interacting transactivator Mutants die shortly after birth, spongiotrophoblast layer irregular in shape and enlarged (Rodriguez et al, 2004) Cited 2 CBP/p300-interacting transactivator Mutants die by E14.5 with reduced spongiotrophoblast, glycogen trophoblast cells and TGCs (Withington et al, 2006) , Jaquemar et al, 2003, Tamai et al, 2000 Connexin 31 Connexin; Gap junction protein 60% mutants die between E10.5 and 13.5 TGC number increased, spongiotrophoblast and labyrinth decreased (Kibschull et al, 2004, Plum et al, 2001 Mutants die by E9.5 with disorganized extraembryonic tissues and the ectoplacental and excocoelomic cavities are not formed (Monkley et al, 2000) TGC terminal differentiation…”

“…The Cx31 and Cx31.1 genes encode for connexin gap junction proteins and are involved in maintaining TGC progenitor cells within the ectoplacental cone and spongiotrophoblast (Kibschull et al, 2005;Kibschull et al, 2004;Plum et al, 2001;ZhengFischhofer et al, 2007). Cx31 is expressed at pre-implantation stages, but is restricted to the ectoplacental cone and extraembryonic ectoderm after implantation and then it persists in spongiotrophoblast (Plum et al, 2001).…”

“…Cx31 is expressed at pre-implantation stages, but is restricted to the ectoplacental cone and extraembryonic ectoderm after implantation and then it persists in spongiotrophoblast (Plum et al, 2001). Cx31.1 is co-expressed with Cx31 at post-implantation stages, except that its expression is suppressed in spongiotrophoblast after E11.5 and persists in glycogen trophoblast cells (Zheng-Fischhofer et al, 2007).…”

Role of gap junctions during early embryo development

“…In an attempt to explore the functional significance of connexin diversity, a targeted gene-inactivation approach has been used. Several of the murine connexin-encoding genes have now been disrupted using homologous recombination in embryonic stem cells: Cx43 (Reaume et al 1995), Cx32 (Nelles et al 1996), Cx37 (Simon et al 1997), Cx46 (Gong et al 1997, Cx40 (Simon et al 1998), Cx26 (Gabriel et al 1998, Cx50 (White et al 1998) Plum et al 2001) and Cx30 (Teubner et al 2003). Each connexin-null mutant results in a unique phenotype, demonstrating a specific physiological role for that connexin in at least a subset of its expression sites (reviewed by Nicholson & Bruzzone 1997, White & Paul 1999.…”

Properties of human connexin 31, which is implicated in hereditary dermatological disease and deafness

“…Cx31 is expressed in testis of adults (9), in placenta, and in developing hindbrain (10); however, no abnormalities of these tissues have been reported in patients with mutations in Cx31. Mice with targeted ablation of the gene for Cx31 show transient abnormalities of placental development and reduced viability of homozygous embryos; however, they have no hearing impairment and no skin abnormalities (11).…”