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doi: 10.1242/10.1242/dev.00473
DEVELOPMENT AND DISEASE |
1 Division of Developmental Biology, National Institute for Medical Research,
Mill Hill, London NW7 1AA, UK
2 Cardiovascular Research and Developmental Biology, The Hospital for Sick
Children and Department of Molecular and Medical Genetics, University of
Toronto, Toronto, ON, Canada
3 Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
4 Department of Genetics, Howard Hughes Medical Institute, Harvard Medical
School, Boston, MA 02115, USA
5 Cardiovascular Division, Howard Hughes Medical Institute, Brigham and Women's
Hospital, Boston, MA 02115, USA
* Author for correspondence (e-mail: mlogan{at}nimr.mrc.ac.uk)
Accepted 10 March 2003
Tbx5 is a T-box transcription factor expressed exclusively in the developing forelimb but not in the developing hindlimb of vertebrates. Tbx5 is first detected in the prospective forelimb mesenchyme prior to overt limb bud outgrowth and its expression is maintained throughout later limb development stages. Direct evidence for a role of Tbx5 in forelimb development was provided by the discovery that mutations in human TBX5 cause Holt-Oram Syndrome (HOS), a dominant disorder characterised predominantly by upper(fore) limb defects and heart abnormalities. Misexpression studies in the chick have demonstrated a role for this gene in limb-type specification. Using a conditional knockout strategy in the mouse to delete Tbx5 gene function in the developing forelimb, we demonstrate that this gene is also required at early limb bud stages for forelimb bud development. In addition, by misexpressing dominant-negative and dominant-activated forms of Tbx5 in the chick wing we provide evidence that this gene is also required at later stages of limb bud development for continued limb outgrowth. Our results provide a context to understand the defects observed in HOS caused by haploinsufficiency of TBX5 in human. Moreover, our results also demonstrate that limb bud outgrowth and specification of limb identity are linked by a requirement for Tbx5.
Key words: Limb development, Limb-type identity, Tbx5, T-box genes, Mouse, Chick
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