Targeted deletion of Hand2 in cardiac neural crest-derived cells influences cardiac gene expression and outflow tract development

Kristen L. Holler, Tyler J. Hendershot, Sophia E. Troy, Joshua W. Vincentz, Anthony Firulli, Marthe J. Howard

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

The basic helix-loop-helix DNA binding protein Hand2 has critical functions in cardiac development both in neural crest-derived and mesoderm-derived structures. Targeted deletion of Hand2 in the neural crest has allowed us to genetically dissect Hand2-dependent defects specifically in outflow tract and cardiac cushion independent of Hand2 functions in mesoderm-derived structures. Targeted deletion of Hand2 in the neural crest results in misalignment of the aortic arch arteries and outflow tract, contributing to development of double outlet right ventricle (DORV) and ventricular septal defects (VSD). These neural crest-derived developmental anomalies are associated with altered expression of Hand2-target genes we have identified by gene profiling. A number of Hand2 direct target genes have been identified using ChIP and ChIP-on-chip analyses. We have identified and validated a number of genes related to cell migration, proliferation/cell cycle and intracellular signaling whose expression is affected by Hand2 deletion in the neural crest and which are associated with development of VSD and DORV. Our data suggest that Hand2 is a multifunctional DNA binding protein affecting expression of target genes associated with a number of functional interactions in neural crest-derived cells required for proper patterning of the outflow tract, generation of the appropriate number of neural crest-derived cells for elongation of the conotruncus and cardiac cushion organization. Our genetic model has made it possible to investigate the molecular genetics of neural crest contributions to outflow tract morphogenesis and cell differentiation.

Original languageEnglish
Pages (from-to)291-304
Number of pages14
JournalDevelopmental Biology
Volume341
Issue number1
DOIs
StatePublished - May 2010

Fingerprint

Neural Crest
Gene Expression
Double Outlet Right Ventricle
Ventricular Heart Septal Defects
DNA-Binding Proteins
Mesoderm
Genes
Genetic Models
Thoracic Aorta
Morphogenesis
Cell Movement
Molecular Biology
Cell Differentiation
Cell Cycle
Arteries
Cell Proliferation

Keywords

  • BHLH
  • Cardiac cushion
  • Cell type-specific gene regulation
  • Gene microarray
  • Hand2(dHand)
  • Heart
  • Neural crest
  • Outflow tract

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology
  • Molecular Biology

Cite this

Targeted deletion of Hand2 in cardiac neural crest-derived cells influences cardiac gene expression and outflow tract development. / Holler, Kristen L.; Hendershot, Tyler J.; Troy, Sophia E.; Vincentz, Joshua W.; Firulli, Anthony; Howard, Marthe J.

In: Developmental Biology, Vol. 341, No. 1, 05.2010, p. 291-304.

Research output: Contribution to journalArticle

Holler, Kristen L. ; Hendershot, Tyler J. ; Troy, Sophia E. ; Vincentz, Joshua W. ; Firulli, Anthony ; Howard, Marthe J. / Targeted deletion of Hand2 in cardiac neural crest-derived cells influences cardiac gene expression and outflow tract development. In: Developmental Biology. 2010 ; Vol. 341, No. 1. pp. 291-304.
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