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Hand2 function in second heart field progenitors is essential for cardiogenesis.

Cardiogenesis involves the contributions of multiple progenitor pools, including mesoderm-derived cardiac progenitors known as the first and second heart fields. Disruption of genetic pathways regulating individual subsets of cardiac progenitors likely underlies many forms of human cardiac malformations. Hand2 is a member of the basic helix loop helix (bHLH) family of transcription factors and is expressed in numerous cell lineages that contribute to the developing heart. However, the early embryonic lethality of Hand2-null mice has precluded lineage-specific study of its function in myocardial progenitors. Here, we generated and used a floxed allele of Hand2 to ablate its expression in specific cardiac cell populations at defined developmental points. We found that Hand2 expression within the mesoderm-derived second heart field progenitors was required for their survival and deletion in this domain recapitulated the complete Hand2-null phenotype. Loss of Hand2 at later stages of development and in restricted domains of the second heart field revealed a spectrum of cardiac anomalies resembling forms of human congenital heart disease. Molecular analyses of Hand2 mutant cells revealed several genes by which Hand2 may influence expansion of the cardiac progenitors. These findings demonstrate that Hand2 is essential for survival of second heart field progenitors and that the graded loss of Hand2 function in this cardiac progenitor pool can cause a spectrum of congenital heart malformation.

Pubmed ID: 21185281

Authors

  • Tsuchihashi T
  • Maeda J
  • Shin CH
  • Ivey KN
  • Black BL
  • Olson EN
  • Yamagishi H
  • Srivastava D

Journal

Developmental biology

Publication Data

March 1, 2011

Associated Grants

  • Agency: NCRR NIH HHS, Id: C06 RR018928
  • Agency: NHLBI NIH HHS, Id: P01 HL089707
  • Agency: NHLBI NIH HHS, Id: P01 HL089707-01A1
  • Agency: NHLBI NIH HHS, Id: P01 HL089707-02
  • Agency: NHLBI NIH HHS, Id: P01 HL089707-03
  • Agency: NHLBI NIH HHS, Id: P01 HL089707-04
  • Agency: NHLBI NIH HHS, Id: R01 HL057181
  • Agency: NHLBI NIH HHS, Id: R01 HL057181-14
  • Agency: NHLBI NIH HHS, Id: R01 HL057181-14W1
  • Agency: NHLBI NIH HHS, Id: R01 HL057181-15
  • Agency: NHLBI NIH HHS, Id: R01 HL057181-16
  • Agency: NHLBI NIH HHS, Id: R01 HL062591
  • Agency: NHLBI NIH HHS, Id: R01 HL062591-08
  • Agency: NHLBI NIH HHS, Id: R01 HL062591-09
  • Agency: NHLBI NIH HHS, Id: R01 HL064658
  • Agency: NHLBI NIH HHS, Id: R01 HL064658-11
  • Agency: NHLBI NIH HHS, Id: R01 HL077439
  • Agency: NHLBI NIH HHS, Id: R01 HL077439-06W1
  • Agency: NHLBI NIH HHS, Id: R01 HL077439-07
  • Agency: NHLBI NIH HHS, Id: R01 HL077439-08
  • Agency: NHLBI NIH HHS, Id: R01 HL080592
  • Agency: NHLBI NIH HHS, Id: R01 HL080592-05
  • Agency: NHLBI NIH HHS, Id: R01 HL080592-06
  • Agency: NHLBI NIH HHS, Id: R01 HL093039
  • Agency: NHLBI NIH HHS, Id: R01 HL093039-01A1W1
  • Agency: NHLBI NIH HHS, Id: R01 HL093039-02
  • Agency: NHLBI NIH HHS, Id: R01 HL093039-03
  • Agency: NHLBI NIH HHS, Id: R37 HL053351
  • Agency: NHLBI NIH HHS, Id: R37 HL053351-13
  • Agency: NHLBI NIH HHS, Id: R37 HL053351-14
  • Agency: NHLBI NIH HHS, Id: R37 HL053351-15

Mesh Terms

  • Alleles
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Survival
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Heart
  • Mice
  • Mice, Inbred C57BL
  • Pharynx
  • Stem Cells