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Absence of connexin43 and connexin45 does not disturb pre- and peri-implantation development

Published online by Cambridge University Press:  21 July 2015

Kiyomasa Nishii ,
Yasushi Kobayashi  and
Yosaburo Shibata
Kiyomasa Nishii*
Affiliation:
Department of Anatomy and Neurobiology, National Defense Medical College, 3–2 Namiki, Tokorozawa, Saitama 359–8513, Japan.
Yasushi Kobayashi
Affiliation:
Department of Anatomy and Neurobiology, National Defense Medical College, 3–2 Namiki, Tokorozawa, Saitama 359–8513, Japan.
Yosaburo Shibata
Affiliation:
Fukuoka Prefectural University, 4395 Ita, Tagawa, Fukuoka 825–8585, Japan.
*
All correspondence to: Kiyomasa Nishii. Department of Anatomy and Neurobiology, National Defense Medical College, 3–2 Namiki, Tokorozawa, Saitama 359–8513, Japan. e-mail: nishii@ndmc.ac.jp
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Summary

Gap junctional intercellular communication is assumed to play an important role during pre- and peri-implantation development. In this study, we eliminated connexin43 (Cx43) and connexin45 (Cx45), major gap junctional proteins in the pre- and peri-implantation embryo. We generated Cx43−/−Cx45−/− embryos by Cx43+/−Cx45+/− intercrossing, because mice deficient in Cx43 (Cx43−/−) exhibit perinatal lethality and those deficient in Cx45 (Cx45−/−) exhibit early embryonic lethality. Wild-type, Cx43−/−, Cx45−/−, and Cx43−/−Cx45−/− blastocysts all showed similar outgrowths in in vitro culture. Moreover, Cx43−/−Cx45−/− embryos were obtained at the expected Mendelian ratio up to embryonic day 9.5, when the Cx45−/− mutation proved lethal. The Cx43−/−Cx45−/− embryos seemed to have no additional developmental abnormalities in comparison with the single knockout strains. Thus, pre- and peri-implantation development does not require Cx43 and Cx45. Other gap junctional proteins are expressed around these stages and these may compensate for the lack of Cx43 and Cx45.

Keywords

Blastocyst cultureConnexin43Connexin45KnockoutPeri-implantation development
Type
Research Article
Information
Zygote , Volume 24 , Issue 3 , June 2016 , pp. 457 - 464
Copyright
Copyright © Cambridge University Press 2015 

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References

Alcoléa, S., Théveniau-Ruissy, M., Jarry-Guichard, T., Marics, I., Tzouanacou, E., Chauvin, J.P., Briand, J.P., Moorman, A.F., Lamers, W.H. & Gros, D.B. (1999). Downregulation of connexin 45 gene products during mouse heart development. Circ. Res. 84, 1365–79.CrossRefGoogle ScholarPubMed
Becker, D.L., Evans, W.H., Green, C.R. & Warner, A. (1995). Functional analysis of amino acid sequences in connexin43 involved in intercellular communication through gap junctions. J. Cell Sci. 108, 1455–67.Google Scholar
Bevilacqua, A., Loch-Caruso, R. & Erickson, R.P. (1989). Abnormal development and dye coupling produced by antisense RNA to gap junction protein in mouse preimplantation embryos. Proc. Natl. Acad. Sci. USA 86, 5444–8.Google Scholar
Cohen-Salmon, M., Ott, T., Michel, V., Hardelin, J.P., Perfettini, I., Eybalin, M., Wu, T., Marcus, D.C., Wangemann, P., Willecke, K. & Petit, C. (2002). Targeted ablation of connexin26 in the inner ear epithelial gap junction network causes hearing impairment and cell death. Curr. Biol. 12, 1106–11.Google Scholar
Dahl, E., Winterhager, E., Reuss, B., Traub, O., Butterweck, A. & Willecke, K. (1996). Expression of the gap junction proteins connexin31 and connexin43 correlates with communication compartments in extraembryonic tissues and in the gastrulating mouse embryo, respectively. J. Cell Sci. 109, 191–7.Google Scholar
Darrow, B.J., Laing, J.G., Lampe, P.D., Saffitz, J.E. & Beyer, E.C. (1995). Expression of multiple connexins in cultured neonatal rat ventricular myocytes. Circ. Res. 76, 381–7.Google Scholar
Davies, T.C., Barr, K.J., Jones, D.H., Zhu, D. & Kidder, G.M. (1996). Multiple members of the connexin gene family participate in preimplantation development of the mouse. Dev. Genet. 18, 234–43.3.0.CO;2-A>CrossRefGoogle ScholarPubMed
De Sousa, P.A., Valdimarsson, G., Nicholson, B.J. & Kidder, G.M. (1993). Connexin trafficking and the control of gap junction assembly in mouse preimplantation embryos. Development 117, 1355–67.Google Scholar
De Sousa, P.A., Juneja, S.C., Caveney, S., Houghton, F.D., Davies, T.C., Reaume, A.G., Rossant, J. & Kidder, G.M. (1997). Normal development of preimplantation mouse embryos deficient in gap junctional coupling. J. Cell Sci. 110, 1751–18.Google Scholar
Ducibella, T. & Anderson, E. (1975). Cell shape and membrane changes in the eight-cell mouse embryo: prerequisites for morphogenesis of the blastocyst. Dev. Biol. 47, 45–58.Google Scholar
Egashira, K., Nishii, K., Nakamura, K., Kumai, M., Morimoto, S. & Shibata, Y. (2004). Conduction abnormality in gap junction protein connexin45-deficient embryonic stem cell-derived cardiac myocytes. Anat. Rec. A Discov. Mol. Cell Evol. Biol. 280, 973–9.Google Scholar
Grümmer, R., Reuss, B. & Winterhager, E. (1996). Expression pattern of different gap junction connexins is related to embryo implantation. Int. J. Dev. Biol. 40, 361–7.Google Scholar
Gutstein, D.E., Morley, G.E., Tamaddon, H., Vaidya, D., Schneider, M.D., Chen, J., Chien, K.R., Stuhlmann, H. & Fishman, G.I. (2001a). Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43. Circ. Res. 88, 333–9.Google Scholar
Gutstein, D.E., Morley, G.E., Vaidya, D., Liu, F., Chen, F.L., Stuhlmann, H. & Fishman, G.I. (2001b). Heterogeneous expression of Gap junction channels in the heart leads to conduction defects and ventricular dysfunction. Circulation 104, 1194–9.Google Scholar
Hatler, J.M., Essner, J.J. & Johnson, R.G. (2009). A gap junction connexin is required in the vertebrate left-right organizer. Dev. Biol. 336, 183–91.CrossRefGoogle ScholarPubMed
Houghton, F.D. (2005). Role of gap junctions during early embryo development. Reproduction 129, 129–35.Google Scholar
Houghton, F.D., Thönnissen, E., Kidder, G.M., Naus, C.C.G., Willecke, K. & Winterhager, E. (1999). Doubly mutant mice, deficient in connexin32 and -43, show normal prenatal development of organs where the two gap junction proteins are expressed in the same cells. Dev. Genet. 24, 5–12.Google Scholar
Houghton, F.D., Barr, K.J., Walter, G., Gabriel, H.D., Grümmer, R., Traub, O., Leese, H.J., Winterhager, E. & Kidder, G.M. (2002). Functional significance of gap junctional coupling in preimplantation development. Biol. Reprod. 66, 1403–12.CrossRefGoogle ScholarPubMed
Juneja, S.C., Barr, K.J., Enders, G.C. & Kidder, G.M. (1999). Defects in the germ line and gonads of mice lacking connexin43. Biol. Reprod. 60, 1263–70.CrossRefGoogle ScholarPubMed
Kanady, J.D., Dellinger, M.T., Munger, S.J., Witte, M.H. & Simon, A.M. (2011). Connexin37 and Connexin43 deficiencies in mice disrupt lymphatic valve development and result in lymphatic disorders including lymphedema and chylothorax. Dev. Biol. 354, 253–66.Google Scholar
Kaufman, M.H. (1992). The Atlas of Mouse Development. London: Academic Press.Google Scholar
Kibschull, M., Magin, T.M., Traub, O. & Winterhager, E. (2005). Cx31 and Cx43 double-deficient mice reveal independent functions in murine placental and skin development. Dev. Dyn. 233, 853–63.Google Scholar
Krüger, O., Plum, A., Kim, J.S., Winterhager, E., Maxeiner, S., Hallas, G., Kirchhoff, S., Traub, O., Lamers, W.H. & Willecke, K. (2000). Defective vascular development in connexin 45-deficient mice. Development 127, 4179–93.Google Scholar
Kumai, M., Nishii, K., Nakamura, K., Takeda, N., Suzuki, M. & Shibata, Y. (2000). Loss of connexin45 causes a cushion defect in early cardiogenesis. Development 127, 3501–12.CrossRefGoogle ScholarPubMed
Lee, S., Gilula, N.B. & Warner, A.E. (1987). Gap junctional communication and compaction during preimplantation stages of mouse development. Cell 51, 851–60.Google Scholar
Levin, M. (2007). Gap junctional communication in morphogenesis. Prog. Biophys. Mol. Biol. 94, 186–206.Google Scholar
Liao, Y., Day, K.H., Damon, D.N. & Duling, B.R. (2001). Endothelial cell-specific knockout of connexin 43 causes hypotension and bradycardia in mice. Proc. Natl. Acad. Sci USA 98, 9989–94.Google Scholar
Lo, C.W. & Gilula, N.B. (1979a). Gap junctional communication in the post-implantation mouse embryo. Cell 18, 411–22.CrossRefGoogle ScholarPubMed
Lo, C.W. & Gilula, N.B. (1979b). Gap junctional communication in the preimplantation mouse embryo. Cell 18, 399–409.Google Scholar
Malassiné, A. & Cronier, L. (2005). Involvement of gap junctions in placental functions and development. Biochim. Biophys. Acta 1719, 117–24.Google Scholar
Martinez, A.D., Hayrapetyan, V., Moreno, A.P. & Beyer, E.C. (2002). Connexin43 and connexin45 form heteromeric gap junction channels in which individual components determine permeability and regulation. Circ. Res. 90, 1100–7.Google Scholar
Maxeiner, S., Dedek, K., Janssen-Bienhold, U., Ammermüller, J., Brune, H., Kirsch, T., Pieper, M., Degen, J., Krüger, O., Willecke, K. & Weiler, R. (2005). Deletion of connexin45 in mouse retinal neurons disrupts the rod/cone signaling pathway between AII amacrine and ON cone bipolar cells and leads to impaired visual transmission. J. Neurosci. 25, 566–76.Google Scholar
Nishii, K., Kumai, M. & Shibata, Y. (2001). Regulation of the epithelial-mesenchymal transformation through gap junction channels in heart development. Trends Cardiovasc. Med. 11, 213–8.Google Scholar
Nishii, K., Kumai, M., Egashira, K., Miwa, T., Hashizume, K., Miyano, Y. & Shibata, Y. (2003). Mice lacking connexin45 conditionally in cardiac myocytes display embryonic lethality similar to that of germline knockout mice without endocardial cushion defect. Cell Commun. Adhes. 10, 365–9.Google Scholar
Nishii, K., Shibata, Y. & Kobayashi, Y. (2014). Connexin mutant embryonic stem cells and human diseases. World J. Stem Cells 6, 571–8.Google Scholar
Nishii, K., Tsuzuki, T., Kumai, M., Takeda, N., Koga, H., Aizawa, S., Nishimoto, T. & Shibata, Y. (1999). Abnormalities of developmental cell death in Dad1-deficient mice. Genes Cells 4, 243–52.Google Scholar
Plum, A., Winterhager, E., Pesch, J., Lautermann, J., Hallas, G., Rosentreter, B., Traub, O., Herberhold, C. & Willecke, K. (2001). Connexin31-deficiency in mice causes transient placental dysmorphogenesis but does not impair hearing and skin differentiation. Dev. Biol. 231, 334–47.Google Scholar
Reaume, A.G., de Sousa, P.A., Kulkarni, S., Langille, B.L., Zhu, D., Davies, T.C., Juneja, S.C., Kidder, G.M. & Rossant, J. (1995). Cardiac malformation in neonatal mice lacking connexin43. Science 267, 1831–4.Google Scholar
Reuss, B., Hellmann, P., Traub, O., Butterweck, A. & Winterhager, E. (1997). Expression of connexin31 and connexin43 genes in early rat embryos. Dev. Genet. 21, 82–90.Google Scholar
Schrickel, J.W., Kreuzberg, M.M., Ghanem, A., Kim, J.S., Linhart, M., Andrié, R., Tiemann, K., Nickenig, G., Lewalter, T. & Willecke, K. (2009). Normal impulse propagation in the atrioventricular conduction system of Cx30.2/Cx40 double deficient mice. J. Mol. Cell. Cardiol. 46, 644–52.Google Scholar
Seki, A., Nishii, K. & Hagiwara, N. (2015). Gap junctional regulation of pressure, fluid force, and electrical fields in the epigenetics of cardiac morphogenesis and remodeling. Life Sci. 129, 27–34.Google Scholar
Simon, A.M. & McWhorter, A.R. (2002). Vascular abnormalities in mice lacking the endothelial gap junction proteins connexin37 and connexin40. Dev. Biol. 251, 206–20.Google Scholar
Simon, A.M., McWhorter, A.R., Dones, J.A., Jackson, C.L. & Chen, H. (2004). Heart and head defects in mice lacking pairs of connexins. Dev. Biol. 265, 369–83.Google Scholar
Theis, M., de Wit, C., Schlaeger, T. M., Eckardt, D., Krüger, O., Döring, B., Risau, W., Deutsch, U., Pohl, U. & Willecke, K. (2001). Endothelium-specific replacement of the connexin43 coding region by a lacZ reporter gene. Genesis 29, 1–13.Google Scholar
Vance, M.M. & Wiley, L.M. (1999). Gap junction intercellular communication mediates the competitive cell proliferation disadvantage of irradiated mouse preimplantation embryos in aggregation chimeras. Radiat. Res. 152, 544–51.Google Scholar
Vandenberg, L.N. & Levin, M. (2013). A unified model for left-right asymmetry? Comparison and synthesis of molecular models of embryonic laterality. Dev. Biol. 379, 1–15.Google Scholar
Wörsdörfer, P., Maxeiner, S., Markopoulos, C., Kirfel, G., Wulf, V., Auth, T., Urschel, S., von Maltzahn, J. & Willecke, K. (2008). Connexin expression and functional analysis of gap junctional communication in mouse embryonic stem cells. Stem Cells 26, 431–9.Google Scholar
Xia, C.H., Cheng, C., Huang, Q., Cheung, D., Li, L., Dunia, I., Benedetti, L.E., Horwitz, J. & Gong, X. (2006). Absence of alpha3 (Cx46) and alpha8 (Cx50) connexins leads to cataracts by affecting lens inner fiber cells. Exp. Eye Res. 83, 688–96.Google Scholar
Yamanaka, S. (2012). Induced pluripotent stem cells: past, present, and future. Cell Stem Cell 10, 678–84.Google Scholar
Yu, J.N., Xue, C.Y., Wang, X.G., Lin, F., Liu, C.Y., Lu, F.Z. & Liu, H.L. (2009). 5-AZA-2′-deoxycytidine (5-AZA-CdR) leads to down-regulation of Dnmt1o and gene expression in preimplantation mouse embryos. Zygote 17, 137–45.Google Scholar