title: Nkx2-5 suppresses the proliferation of atrial myocytes and conduction system.
abstract: BACKGROUND
  Tight control of cardiomyocyte proliferation is essential for the formation of four-chambered heart. Although human mutation of NKX2-5 is linked to septal defects and atrioventricular conduction abnormalities, early lethality and hemodynamic alteration in the mutant models have caused controversy as to whether Nkx2-5 regulates cardiomyocyte proliferation.
  
  
  OBJECTIVE
  In this study, we circumvented these limitations by atrial-restricted deletion of Nkx2-5.
  
  
  RESULTS
  Atrial-specific Nkx2-5 mutants died shortly after birth with hyperplastic working myocytes and conduction system including two nodes and internodal tracts. Multicolor reporter analysis revealed that Nkx2-5-null cardiomyocytes displayed clonal proliferative activity throughout the atria, indicating the suppressive role of Nkx2-5 in cardiomyocyte proliferation after chamber ballooning stages. Transcriptome analysis revealed that aberrant activation of Notch signaling underlies hyperproliferation of mutant cardiomyocytes, and forced activation of Notch signaling recapitulates hyperproliferation of working myocytes but not the conduction system.
  
  
  CONCLUSIONS
  Collectively, these data suggest that Nkx2-5 regulates the proliferation of atrial working and conduction myocardium in coordination with Notch pathway.
authors.affiliation: From the Department of Molecular Cell and Developmental Biology (Y.N., D.A.Y., H.N., A.J., M.P., A.N.), Departments of Pediatrics and Molecular Cell and Integrative Physiology, David Geffen School of Medicine (M.T.), Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research (H.N., M.P., A.N.), Department of Physiology, David Geffen School of Medicine (M.C.J., K.P.R.), Molecular Biology Institute (M.P.), Institute of Genomics and Proteomics (M.P.), and Jonsson Comprehensive Cancer Center (A.N.), University of California, Los Angeles, Los Angeles, CA.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nakashima
authors.forename: Diana A
authors.initials: DA
authors.lastname: Yanez
authors.forename: Marlin
authors.initials: M
authors.lastname: Touma
authors.forename: Haruko
authors.initials: H
authors.lastname: Nakano
authors.forename: Artur
authors.initials: A
authors.lastname: Jaroszewicz
authors.forename: Maria C
authors.initials: MC
authors.lastname: Jordan
authors.forename: Matteo
authors.initials: M
authors.lastname: Pellegrini
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Roos
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakano
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D006325:Heart Atria / Q000166:cytology / Q000378:metabolism*; D006329:Heart Conduction System / Q000166:cytology / Q000378:metabolism*; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000502:physiology; D051880:Receptors, Notch / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; D051880:Receptors, Notch; D014157:Transcription Factors
keywords: Nkx2-5; Notch; atrial septal defect; atrioventricular block; congenital cardiac defect; internodal tract; mitosis