TBX5 transcription factor regulates cell proliferation during cardiogenesis

Mutations in human TBX5, a member of the T-box transcription factor gene fa mily, 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 i n vitro and in vivo. TBX5 inhibited cell proliferation of D17 canine osteos arcoma 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 e ffect. Overexpression of TBX5 in embryonic chick hearts showed that TBX5 in hibits myocardial growth and trabeculation. TBX5 effects in vivo were aboli shed by Gly80Arg missense mutation of the 5' end of the T-box. PCNA analysi s in transgenic chick hearts revealed that TBX5 overexpression does suppres s embryonic cardiomyocyte proliferation in vivo. Inhibitory effects of TBX5 on cardiomyocyte proliferation include a noncell autonomous process in vit ro and in vivo. TBX5 inhibited proliferation of both nontransgenic cells co cultured with transgenic cells in vitro and nontransgenic cardiomyocytes in transgenic chick hearts with mosaic expression of TBX5 in vivo. Immunohist ochemical studies of human embryonic tissues, including hearts, also demons trated 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. (C) 2001 Academic Press.