An endocardial pathway involving Tbx5, Gata4, and Nos3 required for atrial septum formation.

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  • Additional Information
    • Source:
      Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : National Academy of Sciences
    • Subject Terms:
      Atrial Septum/*cytology ; Endocardium/*cytology ; GATA4 Transcription Factor/*physiology ; Heart Diseases/*congenital ; Nitric Oxide Synthase Type III/*physiology ; T-Box Domain Proteins/*physiology; Animals ; Atrial Septum/pathology ; Cell Survival ; Endocardium/pathology ; Haploinsufficiency ; Heart Defects, Congenital/etiology ; Heart Defects, Congenital/genetics ; Mice ; Phenotype ; T-Box Domain Proteins/analysis
    • Abstract:
      In humans, septal defects are among the most prevalent congenital heart diseases, but their cellular and molecular origins are not fully understood. We report that transcription factor Tbx5 is present in a subpopulation of endocardial cells and that its deletion therein results in fully penetrant, dose-dependent atrial septal defects in mice. Increased apoptosis of endocardial cells lacking Tbx5, as well as neighboring TBX5-positive myocardial cells of the atrial septum through activation of endocardial NOS (Nos3), is the underlying mechanism of disease. Compound Tbx5 and Nos3 haploinsufficiency in mice worsens the cardiac phenotype. The data identify a pathway for endocardial cell survival and unravel a cell-autonomous role for Tbx5 therein. The finding that Nos3, a gene regulated by many congenital heart disease risk factors including stress and diabetes, interacts genetically with Tbx5 provides a molecular framework to understand gene-environment interaction in the setting of human birth defects.
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    • Grant Information:
      GMH79045 Canada Canadian Institutes of Health Research; MOP13057 Canada Canadian Institutes of Health Research
    • Accession Number:
      0 (GATA4 Transcription Factor)
      0 (T-Box Domain Proteins)
      0 (T-box transcription factor 5)
      EC 1.14.13.39 (Nitric Oxide Synthase Type III)
      EC 1.14.13.39 (Nos3 protein, mouse)
    • Publication Date:
      Date Created: 20101027 Date Completed: 20101230 Latest Revision: 20211020
    • Publication Date:
      20240829
    • Accession Number:
      PMC2984205
    • Accession Number:
      10.1073/pnas.0914888107
    • Accession Number:
      20974940