Trk C Receptor Signaling Regulates Cardiac Myocyte Proliferation during Early Heart Development in Vivo

• Published in: Developmental biology Vol. 226; no. 2; pp. 180 - 191
• Main Authors: Lin, Michelle I, Das, Indranil, Schwartz, Gregory M, Tsoulfas, Pantelis, Mikawa, Takashi, Hempstead, Barbara L
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.10.2000
• Subjects: Amino Acid Sequence; Animals; Autocrine Communication; cardiac myocyte proliferation; cardiogenesis; Cell Division - drug effects; Chick Embryo; Defective Viruses - genetics; DNA Replication - drug effects; DNA, Complementary - 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; neurotrophin-3; 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; trk C receptor; cardiac myocyte proliferation; trk C receptor; cardiogenesis; neurotrophin-3
• ISSN: 0012-1606; 1095-564X
• 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.