Trk C receptor signaling regulates cardiac myocyte proliferation during early heart development in vivo

Michelle I. Lin, Indranil Das, Gregory M. Schwartz, Pantelis Tsoulfas, Takashi Mikawa, Barbara L. Hempstead

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Neurotrophin-3 (NT-3) is a member of the neurotrophin family of growth factors, best characterized by its survival- and differentiation-inducing effects on developing neurons bearing the trk C receptor tyrosine kinase. Through analysis of NT-3 and trk C gene-targeted mice we have identified NT-3 as critically regulating cardiac septation, valvulogenesis, and conotruncal formation. Although these defects could reflect cardiac neural crest dysfunction, the expression of NT-3 and trk C by cardiac myocytes prior to neural crest migration prompted analysis of cell-autonomous actions of NT-3 on cardiac myocytes. Retroviral-mediated overexpression of truncated trk C receptor lacking kinase activity was used to inhibit activation of trk C by endogenous NT-3, during early heart development in ovo. During the first week of chicken development, expression of truncated trk C reduced myocyte clone size by more than 60% of control clones. Direct mitogenic actions of NT-3 on embryonic cardiac myocytes were demonstrated by analysis of BrdU incorporation or PCNA immunoreactivity in control and truncated trk C-expressing clones. Inhibition of trk C signaling reduced cardiac myocyte proliferation during the first week of development, but had no effect at later times. These studies demonstrate that endogenous NT-3:trk C signaling regulates cardiac myocyte proliferation during cardiac looping and the establishment of ventricular trabeculation but that myocyte proliferation becomes NT-3 independent during the second week of embryogenesis. (C) 2000 Academic Press.

Original languageEnglish (US)
Pages (from-to)180-191
Number of pages12
JournalDevelopmental Biology
Volume226
Issue number2
DOIs
StatePublished - Oct 15 2000

Keywords

  • Cardiac myocyte proliferation
  • Cardiogenesis
  • Neurotrophin-3
  • trk C receptor

ASJC Scopus subject areas

  • Developmental Biology

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