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First published online 20 April 2005
doi: 10.1242/dev.01799
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1 Victor Chang Cardiac Research Institute, St Vincent's Hospital, 384 Victoria
Street, Darlinghurst 2010, New South Wales, Australia
2 Laboratório de Cardiologia Celular e Molecular, Instituto de Biofisica
Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 20941-000,
Brazil
3 Cardiovascular Research Institute, University of California, San Francisco, CA
94143-0130, USA
4 Faculties of Medicine and Life Sciences, University of New South Wales,
Kensington 2056, New South Wales, Australia
Author for correspondence (e-mail:
r.harvey{at}victorchang.unsw.edu.au)
Accepted 21 February 2005
The genetic hierarchies guiding lineage specification and morphogenesis of the mammalian embryonic heart are poorly understood. We now show by gene targeting that murine T-box transcription factor Tbx20 plays a central role in these pathways, and has important activities in both cardiac development and adult function. Loss of Tbx20 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 pre-pattern, 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 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.
Key words: T-box, Tbx20, Heart, Nkx2-5, Tbx2, Chamber myocardium, Dilated cardiomyopathy, mice
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