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Molecular and Cellular Biology, June 2008, p. 4052-4067, Vol. 28, No. 12
0270-7306/08/$08.00+0     doi:10.1128/MCB.02100-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Distinct Expression and Function of Alternatively Spliced Tbx5 Isoforms in Cell Growth and Differentiation

Romain Georges,^1,2, Georges Nemer,^1,2,, Martin Morin,^1,2 Chantal Lefebvre,¹ and Mona Nemer^1,2,3*

Research Unit in Cardiac Growth and Differentiation, Institut de Recherches Cliniques de Montréal, Montréal, QC, Canada,¹ Programme de Biologie Moléculaire, Université de Montréal, Montréal, Canada,² Department of Biochemistry, University of Ottawa, Ottawa, Canada³

Received 23 November 2007/ Returned for modification 28 December 2007/ Accepted 31 March 2008

Mutations in the T-box transcription factor Tbx5 cause Holt-Oram syndrome, an autosomal dominant disease characterized by a wide spectrum of cardiac and upper limb defects with variable expressivity. Tbx5 haploinsufficiency has been suggested to be the underlying mechanism, and experimental models are consistent with a dosage-sensitive requirement for Tbx5 in heart development. Here, we report that Tbx5 levels are regulated through alternative splicing that generates, in addition to the known 518-amino-acid protein, a C-terminal truncated isoform. This shorter isoform retains the capacity to bind DNA, but its interaction with Tbx5 collaborators such as GATA-4 is altered. In vivo, the two spliced isoforms are oppositely regulated in a temporal and growth factor-dependent manner and are present in distinct DNA-binding complexes. The expression of the long isoform correlates with growth stimulation, and its reexpression in postnatal transgenic mouse hearts promotes hypertrophy. Conversely, the upregulation of the short but not the long isoform in C2C12 myoblasts leads to growth arrest and cell death. The results provide novel insight into posttranscriptional Tbx5 regulation and point to an important role not only in cell differentiation but also in cell proliferation and organ growth. The data may help analyze genotype-phenotype relations in patients with Holt-Oram syndrome.

Published ahead of print on 7 April 2008.

R.G. and G.N. are co-first authors.

Present address: Department of Biochemistry, American University of Beirut, Beirut, Lebanon.