Nature Genetics 38, 175 - 183 (2005)
Published online: 25 December 2005; | doi:10.1038/ng1707
Cooperative and antagonistic interactions between Sall4 and Tbx5 pattern the mouse limb and heartKazuko Koshiba-Takeuchi1, 2, 3, 7, Jun K Takeuchi1, 2, 3, 7, Eric P Arruda1, 2, 3, 4, Irfan S Kathiriya5, Rong Mo2, Chi-chung Hui2, 4, Deepak Srivastava5, 6
& Benoit G Bruneau1, 2, 31
Programs in Cardiovascular Research, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada. 2
Developmental Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada. 3
The Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario M5S 1A8, Canada. 4
Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. 5
Departments of Pediatrics and Molecular Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9148, USA. 6
Present address: Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California 94158, USA. 7
These authors contributed equally to this work.
Correspondence should be addressed to Benoit G Bruneau bbruneau@sickkids.ca Human mutations in TBX5, a gene encoding a T-box transcription factor, and SALL4, a gene encoding a zinc-finger transcription factor, cause similar upper limb and heart defects. Here we show that Tbx5 regulates Sall4 expression in the developing mouse forelimb and heart; mice heterozygous for a gene trap allele of Sall4 show limb and heart defects that model human disease. Tbx5 and Sall4 interact both positively and negatively to finely regulate patterning and morphogenesis of the anterior forelimb and heart. Thus, a positive and negative feed-forward circuit between Tbx5 and Sall4 ensures precise patterning of embryonic limb and heart and provides a unifying mechanism for heart/hand syndromes.
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