TBX5 transcription factor regulates cell proliferation during cardiogenesis.
Mutations in human TBX5, a member of the T-box transcription factor gene family, cause congenital cardiac septation defects and isomerism in autosomal dominant Holt-Oram syndrome. To determine the cellular function of TBX5 in cardiogenesis, we overexpressed wild-type and mutant human TBX5 isoforms in vitro and in vivo. TBX5 inhibited cell proliferation of D17 canine osteosarcoma cells and MEQC quail cardiomyocyte-like cells in vitro. Mutagenesis of the 5' end of the T-box but not the 3' end of the T-box abolished this effect. Overexpression of TBX5 in embryonic chick hearts showed that TBX5 inhibits myocardial growth and trabeculation. TBX5 effects in vivo were abolished by Gly80Arg missense mutation of the 5' end of the T-box. PCNA analysis in transgenic chick hearts revealed that TBX5 overexpression does suppress embryonic cardiomyocyte proliferation in vivo. Inhibitory effects of TBX5 on cardiomyocyte proliferation include a noncell autonomous process in vitro and in vivo. TBX5 inhibited proliferation of both nontransgenic cells cocultured with transgenic cells in vitro and nontransgenic cardiomyocytes in transgenic chick hearts with mosaic expression of TBX5 in vivo. Immunohistochemical studies of human embryonic tissues, including hearts, also demonstrated that TBX5 expression is inversely related to cellular proliferation. We propose that TBX5 can act as a cellular arrest signal during vertebrate cardiogenesis and thereby participate in modulation of cardiac growth and development.
Hatcher
C J
CJ
Molecular Cardiology Laboratory, Department of Medicine, Cardiology Division, Weill Medical College of Cornell University, 525 E. 68th Street, New York, New York, 10021, USA.
Kim
M S
MS
Mah
C S
CS
Goldstein
M M
MM
Wong
B
B
Mikawa
T
T
Basson
C T
CT
D019943:Amino Acid Substitution; D000818:Animals; D030801:Animals, Genetically Modified; D002455:Cell Division; D002460:Cell Line; D002642:Chick Embryo; D004285:Dogs; D005318:Fetal Heart / Q000166:cytology / Q000502:physiology; D006321:Heart / Q000196:embryology*; D006801:Humans; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D009206:Myocardium / Q000166:cytology*; D012516:Osteosarcoma; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011784:Quail; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D001616:beta-Galactosidase / Q000032:analysis / Q000235:genetics
D018809:Proliferating Cell Nuclear Antigen; D011994:Recombinant Proteins; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D001616:beta-Galactosidase