| Co-Investigator(Kenkyū-buntansha) |
KOKUBO Hiroki National Institute or Genetics, Division of Mammalian Development, Assistant Professor, 系統生物研究センター, 助手 (10270480)
NAKAZAWA Makoto Tokyo Women's Medical University, Department of Pediatric Cardiology, Professor, 医学部, 教授 (10075567)
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| Budget Amount *help |
¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2004: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2003: ¥2,700,000 (Direct Cost: ¥2,700,000)
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| Research Abstract |
Notch signaling is an evolutionary conserved mechanism for cell fate specification and embryonic development in organisms ranging from flies to human. Notch encodes a transmembrane receptor with extracellular epithelial growth factor-like repeats and a short intracellular domain. In vertebrates, Notch signaling is required for normal neurogenesis, fate choices in the inner ear, somitogenesis, myogenesis, limb bud development, left-right asymmetry, lymphoid cell development, and kidney development. Recently a variety of evidence suggests that Notch signaling has an important role during cardiovascular development.
One set of direct transcriptional targets of the Notch signaling pathway in Drosophila and vertebrates is the hairy and enhancer of split-type basic helix-loop-helix genes. We described previously a novel related gene that we called hairy and enhancer of split-related(hesr) gene. Hesr gene products have been reported to be transcriptional repressors of the Notch signaling pathw
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ay. A targeted mutant mice in hesr1 or hesr3 gene have no altered phenotype, however, Aesr2-knockout mice revealed cardiac anomalies. We confirmed the anomalies using echocardiographic analysis, and anatomical, histological, and transmission electro-micrographic findings. The mutant mice showed tricuspid and mitral valve regurgitation, and dysplasia of the atrio-ventricular(AV) valves, a perimembranous ventricular septal defect, a secundum atrial septal defect. These results suggest that hesr2 plays an important role in the formation and function of the AV valves. In addition, hesr2 activity may be important for proper development of cardiomyocytes.
We generated mouse embryos lacking both hesr1 and hesr2. They were embryonic lethal due to severe cardiovascular malformation at 11.5 days postcoitum(dpc). Hesr1/2 double mutants had a single large ventricle, indicating that ventricular septum formation is blocked. At 9.5 dpc the mutant hearts had the compact and trabecular zones in the ventricle, however, the ventricle at 10.5 dpc showed poor trabecular formation due to apoptosis. In addition, few cells underwent endocardial to mesenchymal trasformation in the developing AV cushions. These results demonstrate hesr1 and hesr2 as mediators of Notch signaling are required for the developing heart. Less
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