Tak1, Smad4 and Trim33 redundantly mediate TGF-β3 signaling during palate development.
Tak1, Smad4 and Trim33 redundantly mediate TGF-β3 signaling during palate development.
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DOI：
10.1016/j.ydbio.2014.12.006
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发表时间：
2015-02-15
影响因子：
2.7
通讯作者：
Kaartinen, Vesa
中科院分区：
文献类型：
--
作者：
Lane, Jamie;Yumoto, Kenji;Azhar, Mohamad;Ninomiya-Tsuji, Jun;Inagaki, Maiko;Hu, Yingling;Deng, Chu-Xia;Kim, Jieun;Mishina, Yuji;Kaartinen, Vesa
转化生长因子-β 3（Transforming growth factor-β3，TGF-β3）通过诱导腭上皮细胞融合在腭上皮细胞中起关键作用，腭上皮融合失败导致腭裂，腭裂是人类最常见的出生缺陷之一。最近的研究表明，Smad依赖性和Smad非依赖性途径在腭上皮细胞中对TGF-β3信号通路起着冗余作用。然而，这种信号传导介导的详细机制仍有待阐明。我们发现TGF-β激活的激酶-1（Tak 1）和Smad 4在腭上皮融合中存在遗传相互作用。虽然同时废除Tak 1和Smad 4在腭上皮细胞导致的特征性缺陷，在前部和后部的次级腭，这些表型是不那么严重，比在相应的Tgfb 3突变体。此外，我们的研究结果表明，Trim 33，一种新的染色质阅读器和TGF-β信号转导的调节剂，在腭发育过程中与Smad 4合作。与上皮特异性Smad 4突变体不同，上皮特异性Tak 1：Smad 4-和Trim 33：Smad 4-双突变体显示Mmp 13在腭中缘上皮细胞中的表达减少，这表明这两种冗余机制都是适当的TGF-β信号转导所必需的。此外，我们表明，失活的Tak 1在Trim 33：Smad 4双条件敲除导致腭表型，这是相同的上皮特异性Tgfb 3突变体中看到的。综上所述，我们的数据揭示了在腭发育过程中TGF-β信号转导的复杂性，并证明了涉及Smad 4，Tak 1和Trim 33的功能冗余途径调节腭上皮融合。
Transforming growth factor-beta3 (TGF-β3) plays a critical role in palatal epithelial cells by inducing palatal epithelial fusion, failure of which results in cleft palate, one of the most common birth defects in humans. Recent studies have shown that Smad-dependent and Smad-independent pathways work redundantly to transduce TGF-β3 signaling in palatal epithelial cells. However, detailed mechanisms by which this signaling is mediated still remain to be elucidated. Here we show that TGF-β activated kinase-1 (Tak1) and Smad4 interact genetically in palatal epithelial fusion. While simultaneous abrogation of both Tak1 and Smad4 in palatal epithelial cells resulted in characteristic defects in the anterior and posterior secondary palate, these phenotypes were less severe than those seen in the corresponding Tgfb3 mutants. Moreover, our results demonstrate that Trim33, a novel chromatin reader and regulator of TGF-β signaling, cooperates with Smad4 during palatogenesis. Unlike the epithelium-specific Smad4 mutants, epithelium-specific Tak1:Smad4- and Trim33:Smad4-double mutants display reduced expression of Mmp13 in palatal medial edge epithelial cells, suggesting that both of these redundant mechanisms are required for appropriate TGF-β signal transduction. Moreover, we show that inactivation of Tak1 in Trim33:Smad4 double conditional knockouts leads to the palatal phenotypes which are identical to those seen in epithelium-specific Tgfb3 mutants. To conclude, our data reveal added complexity in TGF-β signaling during palatogenesis and demonstrate that functionally redundant pathways involving Smad4, Tak1 and Trim33 regulate palatal epithelial fusion.
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