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First published online 20 April 2005
doi: 10.1242/dev.01827
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1 Cardiovascular Research, The Hospital for Sick Children, Toronto, ON, M5G 1X8,
Canada
2 Developmental Biology, The Hospital for Sick Children, Toronto, ON, M5G 1X8,
Canada
3 The Heart and Stroke/Richard Lewar Centre of Excellence, University of
Toronto, Toronto, ON, M5S 1A8, Canada
4 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University
Avenue, Toronto, ON, M5G 1X5, Canada
5 Cardiovascular Research Institute and Department of Biochemistry and
Biophysics, University of California, San Francisco, CA 94143-0130, USA
6 Department of Molecular and Medical Genetics, University of Toronto, Toronto,
ON, M5S 1A8, Canada
7 Unité de recherche en développement et différenciation
cardiaques, Institut de recherches cliniques de Montréal (IRCM),
Montréal, QC, H2W 1R7, Canada
8 Programme de biologie moléculaire, Faculté des études
supérieures, Université de Montréal, Montréal, QC,
H3C 3J7, Canada
9 Mouse Imaging Centre, The Hospital for Sick Children, 555 University Avenue,
Toronto ON, M5G 1X8, Canada
10 Department of Medical Biophysics, University of Toronto, Toronto, ON, M5S 1A8,
Canada
* Author for correspondence (e-mail: bbruneau{at}sickkids.ca)
Accepted 17 March 2005
To elucidate the function of the T-box transcription factor Tbx20 in mammalian development, we generated a graded loss-of-function series by transgenic RNA interference in entirely embryonic stem cell-derived mouse embryos. Complete Tbx20 knockdown resulted in defects in heart formation, including hypoplasia of the outflow tract and right ventricle, which derive from the anterior heart field (AHF), and decreased expression of Nkx2-5 and Mef2c, transcription factors required for AHF formation. A mild knockdown led to persistent truncus arteriosus (unseptated outflow tract) and hypoplastic right ventricle, entities similar to human congenital heart defects, and demonstrated a critical requirement for Tbx20 in valve formation. Finally, an intermediate knockdown revealed a role for Tbx20 in motoneuron development, specifically in the regulation of the transcription factors Isl2 and Hb9, which are important for terminal differentiation of motoneurons. Tbx20 could activate promoters/enhancers of several genes in cultured cells, including the Mef2c AHF enhancer and the Nkx2-5 cardiac enhancer. The Mef2c AHF enhancer relies on Isl1- and Gata-binding sites. We identified a similar Isl1 binding site in the Nkx2-5 AHF enhancer, which in transgenic mouse embryos was essential for activity in a large part of the heart, including the outflow tract. Tbx20 synergized with Isl1 and Gata4 to activate both the Mef2c and Nkx2-5 enhancers, thus providing a unifying mechanism for gene activation by Tbx20 in the AHF. We conclude that Tbx20 is positioned at a critical node in transcription factor networks required for heart and motoneuron development where it dose-dependently regulates gene expression.
Key words: Heart, Tbx20, T-box, Transcription factors, Mouse, Embryo, Motoneurons, RNAi, Optical projection tomography
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