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

Neurotrophin-3 (NT-3) is a member of the neurotrophin family of growth fact ors, best characterized by its survival- and differentiation-inducing effec ts on developing neurons bearing the trk C receptor tyrosine kinase. Throug h analysis of NT-3 and trk C gene-targeted mice we have identified NT-3 as critically regulating cardiac septation, valvulogenesis, and conotruncal fo rmation. Although these defects could reflect cardiac neural crest dysfunct ion, the expression of NT-3 and trk C by cardiac myocytes prior to neural c rest migration prompted analysis of cell-autonomous actions of NT-3 on card iac myocytes. Retroviral-mediated overexpression of truncated trk C recepto r lacking kinase activity was used to inhibit activation of trk C by endoge nous NT-3, during early heart development in ovo. During the first week of chicken development, expression of truncated trk C reduced myocyte clone si ze by more than 60% of control clones. Direct mitogenic actions of NT-3 on embryonic cardiac myocytes were demonstrated by analysis of BrdU incorporat ion or PCNA immunoreactivity in control and truncated trk C-expressing clon es. Inhibition of trk C signaling reduced cardiac myocyte proliferation dur ing 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 ventr icular trabeculation but that myocyte proliferation becomes NT-3 independen t during the second week of embryogenesis. (C) 2000 Academic Press.