Distinct expression and function of alternatively spliced Tbx5 isoforms in cell growth and differentiation.

[holt-oram syndrome]

Mutations in the T -box transcription factor Tbx 5 cause Holt-Oram syndrome , an autosomal dominant disease characterized by a wide spectrum of cardiac and upper limb defects with variable expressivity . Tbx 5 haploinsufficiency has been suggested to be the underlying mechanism , and experimental models are consistent with a dosage-sensitive requirement for Tbx 5 in heart development . Here , we report that Tbx 5 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 Tbx 5 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 C 2 C 12 myoblasts leads to growth arrest and cell death . The results provide novel insight into posttranscriptional Tbx 5 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 .