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

Dev Biol. 2000 Oct 15;226(2):180-91. doi: 10.1006/dbio.2000.9850.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Autocrine Communication
  • Cell Division / drug effects
  • Chick Embryo
  • DNA Replication / drug effects
  • DNA, Complementary / genetics
  • Defective Viruses / genetics
  • Fetal Heart / cytology*
  • Fetal Heart / drug effects
  • Fibroblast Growth Factor 1
  • Fibroblast Growth Factor 2 / physiology
  • Genetic Vectors / genetics
  • Molecular Sequence Data
  • Myocardium / cytology*
  • Myocardium / metabolism
  • Neurotrophin 3 / physiology*
  • Peptide Fragments / genetics
  • Peptide Fragments / physiology
  • Proliferating Cell Nuclear Antigen / analysis
  • Receptor, trkC / chemistry
  • Receptor, trkC / deficiency
  • Receptor, trkC / drug effects
  • Receptor, trkC / genetics
  • Receptor, trkC / physiology*
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / physiology
  • Retroviridae / genetics


  • DNA, Complementary
  • Neurotrophin 3
  • Peptide Fragments
  • Proliferating Cell Nuclear Antigen
  • Recombinant Fusion Proteins
  • Fibroblast Growth Factor 2
  • Fibroblast Growth Factor 1
  • Receptor, trkC