Murine T-box transcription factor Tbx20 acts as a repressor during heart development, and is essential for adult heart integrity, function and adaptation

Development, May 2005

Fiona A. Stennard, Mauro W. Costa, Donna Lai, Christine Biben, Milena B. Furtado, Mark J. Solloway, David J. McCulley, Christiana Leimena, Jost I. Preis, Sally L. Dunwoodie, et al.

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Murine T-box transcription factor Tbx20 acts as a repressor during heart development, and is essential for adult heart integrity, function and adaptation

Fiona A. Stennard 2 Mauro W. Costa 1 2 Donna Lai 2 Christine Biben 2 Milena B. Furtado 2 Mark J. Solloway 2 David J. McCulley 0 Christiana Leimena 2 Jost I. Preis 2 Sally L. Dunwoodie 2 3 David E. Elliott 2 4 Owen W. J. Prall 2 Brian L. Black 0 Diane Fatkin 2 3 Richard P. Harvey ) 2 3 0 Cardiovascular Research Institute, University of California , San Francisco, CA 94143-0130 , USA 1 Laboratorio de Cardiologia Celular e Molecular, Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro , 20941-000 , Brazil 2 Victor Chang Cardiac Research Institute, St Vincent's Hospital , 384 Victoria Street, Darlinghurst 2010, New South Wales , Australia 3 Faculties of Medicine and Life Sciences, University of New South Wales , Kensington 2056, New South Wales , Australia 4 Present address: The Wellcome Trust/Cancer Research UK, Gurdon Institute of Cancer and Developmental Biology, University of Cambridge , Tennis Court Road, Cambridge CB2 1QR , UK heart development, and is essential for adult heart integrity, - t The genetic hierarchies guiding lineage specification and n morphogenesis of the mammalian embryonic heart are em poorly understood. We now show by gene targeting that p murine T-box transcription factor Tbx20 plays a central o le role in these pathways, and has important activities in both ev cardiac development and adult function. Loss of Tbx20 D results in death of embryos at mid-gestation with grossly abnormal heart morphogenesis. Underlying these disturbances was a severely compromised cardiac transcriptional program, defects in the molecular prepattern, reduced expansion of cardiac progenitors and a block to chamber differentiation. Notably, Tbx20-null embryos showed ectopic activation of Tbx2 across the whole heart myogenic field. Tbx2 encodes a transcriptional repressor normally expressed in non-chamber myocardium, and in the atrioventricular canal it has been proposed to inhibit chamber-specific gene expression Cardiac development in mammals is guided by an ancient and conserved genetic program (Cripps and Olson, 2002; Harvey, 2002; Zaffran and Frasch, 2002). However, how the cardiac program unfolds, the specific relationships between patterning events and the transcription factor hierarchy, and how cardiomyocyte function impacts on heart form remain poorly understood. Of 18 T-box factor genes identified in mammals, at least six of them (Tbx1/2/3/5/18/20) are expressed in the developing heart (Plageman and Yutzey, 2004). T-box proteins are characterized by the presence of a sequence-specific DNAbinding domain called the T-box (Smith, 1999). During embryogenesis, T-box genes are expressed in restricted and sometimes overlapping domains throughout gastrulation and/or organogenesis, and in some cases roles in controlling through competition with positive factor Tbx5. Our data demonstrate a repressive activity for Tbx20 and place it upstream of Tbx2 in the cardiac genetic program. Thus, hierarchical, repressive interactions between Tbx20 and other T-box genes and factors underlie the primary lineage split into chamber and non-chamber myocardium in the forming heart, an early event upon which all subsequent morphogenesis depends. Additional roles for Tbx20 in adult heart integrity and contractile function were revealed by in-vivo cardiac functional analysis of Tbx20 heterozygous mutant mice. These data suggest that mutations in human cardiac transcription factor genes, possibly including TBX20, underlie both congenital heart disease and adult cardiomyopathies. cell fate and migration have been demonstrated (Chapman and Papaioannou, 1998; Naiche and Papaioannou, 2003; Russ et al., 2000). T-box factors can act up- or downstream of signaling factors of the TGF- (Suzuki et al., 2004), fibroblast growth factor (Brown et al., 2004; Hu et al., 2004; Sakiyama et al., 2003; Yamagishi et al., 2003), sonic hedgehog (Suzuki et al., 2004; Yamagishi et al., 2003) and wingless-related (Takeuchi et al., 2003) superfamilies. Haploinsufficiencies for several human T-box genes have been linked to congenital anomaly syndromes (Bongers et al., 2004; Packham and Brook, 2003). Two of these involve cardiac malformations. Di George syndrome, also occurring as part of chromosome 22q11 deletion syndrome, is characterized by dysmorphogenesis of the cardiac outflow tract (OFT), as well as thymic, splenic and craniofacial abnormalities (Yamagishi and Srivastava, 2003). Holt Oram syndrome is characterized by congenital abnormalities of the upper limbs and heart, the latter involving atrial and ventricular septal defects, tetralogy of Fallot and atrioventricular conduction block (Gruber and Epstein, 2004). Targeted mutation of causative genes in mice has reproduced many aspects of the human cardiac disease phenotypes, thus providing valuable models for understanding underlying mechanisms (Bruneau et al., 2001; Lindsay et al., 2001; Merscher et al., 2001; Yamagishi and Srivastava, 2003). Tbx20 is an ancient m (...truncated)


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Fiona A. Stennard, Mauro W. Costa, Donna Lai, Christine Biben, Milena B. Furtado, Mark J. Solloway, David J. McCulley, Christiana Leimena, Jost I. Preis, Sally L. Dunwoodie, David E. Elliott, Owen W. J. Prall, Brian L. Black, Diane Fatkin, Richard P. Harvey. Murine T-box transcription factor Tbx20 acts as a repressor during heart development, and is essential for adult heart integrity, function and adaptation, Development, 2005, pp. 2451-2462, 132/10, DOI: 10.1242/dev.01799