Tbx5 is required for forelimb bud formation and continued outgrowth
Tbx5 is required for forelimb bud formation and continued outgrowth
复制标题
前肢芽的形成和继续生长需要 Tbx5
DOI：
10.1242/dev.00473
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发表时间：
2003-06-01
期刊：
影响因子：
4.6
通讯作者：
Logan, MPO
中科院分区：
文献类型：
--
作者：
Rallis, C;Bruneau, BG;Logan, MPO
Tbx 5是一种只在脊椎动物前肢发育中表达而在后肢发育中不表达的T-box转录因子。Tbx 5首先在明显的肢芽生长之前在前瞻性前肢间充质中检测到，并且其表达在整个后期肢发育阶段中保持。人类TBX 5突变会导致Holt-Oram综合征（HOS），这是一种主要以上肢（前肢）缺陷和心脏异常为特征的显性疾病，这一发现提供了Tbx 5在前肢发育中作用的直接证据。鸡的错误表达研究已经证明了该基因在肢型特化中的作用。在小鼠中使用条件性敲除策略来删除Tbx 5基因在前肢发育中的功能，我们证明了该基因在前肢芽发育的早期肢芽阶段也是必需的。此外，通过在鸡翅膀中错误表达Tbx 5的显性负和显性激活形式，我们提供了证据表明，该基因在肢芽发育的后期阶段也需要持续的肢体生长。我们的研究结果提供了一个背景，以了解在人类中TBX 5单倍不足引起的HOS中观察到的缺陷。此外，我们的研究结果还表明，肢体芽生长和规格的肢体身份是由Tbx 5的要求。
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.