Hand2 function in second heart field progenitors is essential for cardiogenesis

Takatoshi Tsuchihashi, Jun Maeda, Chong H. Shin, Kathryn N. Ivey, Brian L. Black, Eric N. Olson, Hiroyuki Yamagishi, Deepak Srivastava

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)62-69
Number of pages8
JournalDevelopmental Biology
Volume351
Issue number1
DOIs
Publication statusPublished - 2011 Mar 1

Fingerprint

Mesoderm
Basic Helix-Loop-Helix Transcription Factors
Survival
Congenital Heart Defects
Cell Lineage
Heart Diseases
Alleles
Phenotype
Population
Genes

Keywords

  • Congenital heart disease
  • Hand2
  • Heart development
  • Mouse genetics
  • Second heart field

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology
  • Molecular Biology

Cite this

Tsuchihashi, T., Maeda, J., Shin, C. H., Ivey, K. N., Black, B. L., Olson, E. N., ... Srivastava, D. (2011). Hand2 function in second heart field progenitors is essential for cardiogenesis. Developmental Biology, 351(1), 62-69. https://doi.org/10.1016/j.ydbio.2010.12.023

Hand2 function in second heart field progenitors is essential for cardiogenesis. / Tsuchihashi, Takatoshi; Maeda, Jun; Shin, Chong H.; Ivey, Kathryn N.; Black, Brian L.; Olson, Eric N.; Yamagishi, Hiroyuki; Srivastava, Deepak.

In: Developmental Biology, Vol. 351, No. 1, 01.03.2011, p. 62-69.

Research output: Contribution to journalArticle

Tsuchihashi, T, Maeda, J, Shin, CH, Ivey, KN, Black, BL, Olson, EN, Yamagishi, H & Srivastava, D 2011, 'Hand2 function in second heart field progenitors is essential for cardiogenesis', Developmental Biology, vol. 351, no. 1, pp. 62-69. https://doi.org/10.1016/j.ydbio.2010.12.023
Tsuchihashi T, Maeda J, Shin CH, Ivey KN, Black BL, Olson EN et al. Hand2 function in second heart field progenitors is essential for cardiogenesis. Developmental Biology. 2011 Mar 1;351(1):62-69. https://doi.org/10.1016/j.ydbio.2010.12.023
Tsuchihashi, Takatoshi ; Maeda, Jun ; Shin, Chong H. ; Ivey, Kathryn N. ; Black, Brian L. ; Olson, Eric N. ; Yamagishi, Hiroyuki ; Srivastava, Deepak. / Hand2 function in second heart field progenitors is essential for cardiogenesis. In: Developmental Biology. 2011 ; Vol. 351, No. 1. pp. 62-69.
@article{801e3fd7e4d445cd95748cf5a15ee353,
title = "Hand2 function in second heart field progenitors is essential for cardiogenesis",
abstract = "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.",
keywords = "Congenital heart disease, Hand2, Heart development, Mouse genetics, Second heart field",
author = "Takatoshi Tsuchihashi and Jun Maeda and Shin, {Chong H.} and Ivey, {Kathryn N.} and Black, {Brian L.} and Olson, {Eric N.} and Hiroyuki Yamagishi and Deepak Srivastava",
year = "2011",
month = "3",
day = "1",
doi = "10.1016/j.ydbio.2010.12.023",
language = "English",
volume = "351",
pages = "62--69",
journal = "Developmental Biology",
issn = "0012-1606",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - Hand2 function in second heart field progenitors is essential for cardiogenesis

AU - Tsuchihashi, Takatoshi

AU - Maeda, Jun

AU - Shin, Chong H.

AU - Ivey, Kathryn N.

AU - Black, Brian L.

AU - Olson, Eric N.

AU - Yamagishi, Hiroyuki

AU - Srivastava, Deepak

PY - 2011/3/1

Y1 - 2011/3/1

N2 - 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.

AB - 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.

KW - Congenital heart disease

KW - Hand2

KW - Heart development

KW - Mouse genetics

KW - Second heart field

UR - http://www.scopus.com/inward/record.url?scp=79551684662&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79551684662&partnerID=8YFLogxK

U2 - 10.1016/j.ydbio.2010.12.023

DO - 10.1016/j.ydbio.2010.12.023

M3 - Article

VL - 351

SP - 62

EP - 69

JO - Developmental Biology

JF - Developmental Biology

SN - 0012-1606

IS - 1

ER -