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 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.
Lin
M I
MI
Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA.
Das
I
I
Schwartz
G M
GM
Tsoulfas
P
P
Mikawa
T
T
Hempstead
B L
BL
D000595:Amino Acid Sequence; D000818:Animals; D019898:Autocrine Communication; D002455:Cell Division / Q000187:drug effects; D002642:Chick Embryo; D004261:DNA Replication / Q000187:drug effects; D018076:DNA, Complementary / Q000235:genetics; D003673:Defective Viruses / Q000235:genetics; D005318:Fetal Heart / Q000166:cytology* / Q000187:drug effects; D016220:Fibroblast Growth Factor 1; D016222:Fibroblast Growth Factor 2 / Q000502:physiology; D005822:Genetic Vectors / Q000235:genetics; D008969:Molecular Sequence Data; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D020933:Neurotrophin 3 / Q000502:physiology*; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D020812:Receptor, trkC / Q000737:chemistry / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000502:physiology; D012190:Retroviridae / Q000235:genetics
D018076:DNA, Complementary; D020933:Neurotrophin 3; D010446:Peptide Fragments; D018809:Proliferating Cell Nuclear Antigen; D011993:Recombinant Fusion Proteins; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D020812:Receptor, trkC