Distinct expression and function of alternatively spliced Tbx5 isoforms in cell growth and differentiation
Distinct expression and function of alternatively spliced Tbx5 isoforms in cell growth and differentiation
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DOI：
10.1128/mcb.02100-07
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发表时间：
2008-06-01
影响因子：
5.3
通讯作者：
Nemer, Mona
中科院分区：
文献类型：
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作者：
Georges, Romain;Nemer, Georges;Nemer, Mona
T - 盒转录因子Tbx5的突变会导致霍尔特 - 奥拉姆综合征（Holt - Oram syndrome），这是一种常染色体显性疾病，其特征是具有多种心脏和上肢缺陷，且表现度不一。Tbx5单倍体不足被认为是潜在机制，并且实验模型与心脏发育过程中对Tbx5的剂量敏感需求相符。在此，我们报道Tbx5的水平是通过选择性剪接来调控的，除了产生已知的含518个氨基酸的蛋白质外，还产生一种C末端截短的异构体。这种较短的异构体保留了结合DNA的能力，但其与Tbx5的协同因子（如GATA - 4）的相互作用发生了改变。在体内，这两种剪接异构体以时间和生长因子依赖的方式受到相反的调控，并且存在于不同的DNA结合复合物中。长异构体的表达与生长刺激相关，并且它在出生后转基因小鼠心脏中的重新表达会促进肥大。相反，在C2C12成肌细胞中短异构体（而非长异构体）的上调会导致生长停滞和细胞死亡。这些结果为Tbx5的转录后调控提供了新的见解，并指出其不仅在细胞分化中，而且在细胞增殖和器官生长中都具有重要作用。这些数据可能有助于分析霍尔特 - 奥拉姆综合征患者的基因型 - 表型关系。
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.