title: Connexin45 contributes to global cardiovascular development by establishing myocardial impulse propagation.
abstract: Among gap junction-encoding genes, the loss of connexin (Cx) 45 most profoundly obstructs embryogenesis through an endocardial cushion defect and conduction block. However, the interdependence of these defects is not known, and the details of conduction block have not been elucidated. Here, we examined mouse embryos with a region-specific deletion of Cx45 in the myocardium (CA-Cre; Cx45(flox/flox)) or endothelium (Tie2-Cre; Cx45(flox/flox)). Although the deletion of Cx45 in the myocardium was heterogeneous, the CA-Cre; Cx45(flox/flox) embryos were lethal at the same stage as the constitutive Cx45-deficient (Cx45(-/-)) embryos. We determined the onset and patterns of their conduction block through point-tracking in video recordings of embryonic heart contractions. An incomplete conduction block at the atrioventricular canal appeared at embryonic day (E) 8.5 and was predominant around the lethal E9.5 stage in both the Cx45(-/-) and CA-Cre; Cx45(flox/flox) embryos. Although the Cx45(-/-) hearts showed a consistently severe reduction in atrioventricular conduction velocity, the CA-Cre; Cx45(flox/flox) hearts had delay times within the normal range and showed frequent retrograde conduction. As previously reported, the Cx45(-/-) endocardial cushion was consistently defective, and nuclear factor of activated T-cells cytoplasmic (NFATc)1 within the endocardium showed inactive cytoplasmic distribution. In CA-Cre; Cx45(flox/flox), however, the endocardial cushion was partially formed, with active NFATc1 within the endocardium. There was no developmental abnormality in the Tie2-Cre; Cx45(flox/flox) embryos. These results indicate that myocardial dysfunction is responsible for most of the reported defects in Cx45(-/-), which are alleviated by sporadic Cx45 expression in the CA-Cre; Cx45(flox/flox) myocardium.
authors.affiliation: Department of Anatomy and Neurobiology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan. Electronic address: nishii@ndmc.ac.jp.
authors.forename: Kiyomasa
authors.initials: K
authors.lastname: Nishii
authors.affiliation: Department of Cardiology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Seki
authors.affiliation: Department of Health and Nutrition, Faculty of Health Management, Nagasaki International University, 2825-7 Huis Ten Bosch-cho, Sasebo, Nagasaki 859-3298, Japan.
authors.forename: Madoka
authors.initials: M
authors.lastname: Kumai
authors.affiliation: Department of Clinical Pharmacology, Graduate School of Medical Science, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan.
authors.forename: Sachio
authors.initials: S
authors.lastname: Morimoto
authors.affiliation: Genome Information Research Center, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miwa
authors.affiliation: Department of Cardiology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan.
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Hagiwara
authors.affiliation: Fukuoka Prefectural University, 4395 Ita, Tagawa, Fukuoka 825-8585, Japan.
authors.forename: Yosaburo
authors.initials: Y
authors.lastname: Shibata
authors.affiliation: Department of Anatomy and Neurobiology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan. Electronic address: yasushi@ndmc.ac.jp.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D017630:Connexins / Q000378:metabolism*; D047108:Embryonic Development / Q000502:physiology; D004699:Endocardium / Q000196:embryology* / Q000378:metabolism*; D004727:Endothelium / Q000196:embryology / Q000378:metabolism; D017629:Gap Junctions / Q000378:metabolism; D006321:Heart / Q000196:embryology*; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism
chemical_list: D017630:Connexins; D050778:NFATC Transcription Factors; C082920:connexin 45
keywords: Conduction block; Connexin45; Cushion defect; Heart development