| Project/Area Number |
17390052
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General anatomy (including Histology/Embryology)
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| Research Institution | KYUSHU UNIVERSITY |
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Principal Investigator |
SHIBATA Yosaburo Kyushu University, Faculty of Medical Science, Professor, 大学院医学研究院, 教授 (90037482)
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| Co-Investigator(Kenkyū-buntansha) |
INAI Tetsuichiro Kyushu University, Faculty of Medical Science, Associate Professor, 大学院医学研究院, 助教授 (00264044)
HIROSE Eiji Kyushu University, Faculty of Medical Science, Research Associate, 大学院医学研究院, 助手 (40380620)
NISHII Kiyomasa Tokyo Medical and Dental University, Assistant Professor(COE), 大学院医歯学総合研究科, COE拠点形成特別研究員 (20264020)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥13,900,000 (Direct Cost: ¥13,900,000)
Fiscal Year 2006: ¥6,000,000 (Direct Cost: ¥6,000,000)
Fiscal Year 2005: ¥7,900,000 (Direct Cost: ¥7,900,000)
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| Keywords | gap junction / connexin / knockout mouse / cardiac development / endocardial cushion / heart / gap junction / connexin / gene targeting / NFATc1 / endocardial cushion / atrioventricular block |
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| Research Abstract |
Among gap junction protein connexins, we focused on the function of connexin43 (Cx43) and connexin45 (Cx45) that are the major connexins in cardiac system. First, we analyzed the early myocardial contraction and the cardiac development using Cx43 and Cx45 deficient mice (Cx43-KO and Cx45-KO). We found intriguing differences of phenotypes between two KO mice. Cx43-KO died just after birth but showed coordinated myocardial contraction and formed endocardial cushion. In contrast, Cx45-KO showed initiation of myocardial contraction and partial coordination of contraction at E.8.25 stage, but died within next 24 hours by the atrioventricular contraction block and by the defect in the formation of endocardial cushion. Second, we made conditional KO mice lacking the Cx45 expression specifically in vascular endothelial cells (Cx45-Tie2) and cardiac myocytes (Cx45-CA) respectively, because Cx45 is mainly expressed in these cells. Cx45-CA was lethal due to an atrioventricular contraction block s
… More
imilar to Cx45-KO though the endocardial cushion was formed. Furthermore, Cx43/45 double KO showed the same phenotype as Cx45-KO. These data suggest the functions of Cx43 and Cx45 in the initiation of myocardial contraction and the formation of endocardial cushion as following. (1) Cx43 is scarcely involved in these processes. (2) Lacking Cx45 in myocardial cells induces contraction block. (3) Lacking Cx45 both in myocardial cells and endocardial endothelial cells induces defect in the formation of endocardial cushion.
In addition to these results, the deficiency in the formation of endocardial cushion varied in Cx45-CA mice, suggesting that soluble factor derived from Cx45 expressing cells in heart is essential for these processes. We proposed the new model ; Activation of Ca^<2+> dependent transcription factor NFATc1, which is involved in valve induction in heart development, is critical for the formation of endocardial cushion. In this model, Ca^<2+> wave propagates by passing through Cx45 containing gap junctions and triggers the synchronized activation of Ca^<2+>/calcineurin/NFATc1 system.
Cx45-KO showed moderately coordinated contraction until lethal stage. This suggests another gap junction protein, pannexin that is a vertebrate homologue of innexin for example, might be involved in the formation of the functional gap junction at early stages of cardiac development. This should be addressed afterwards. Less
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