Mice with Tak1 Deficiency in Neural Crest Lineage Exhibit Cleft Palate Associated with Abnormal Tongue Development
Mice with Tak1 Deficiency in Neural Crest Lineage Exhibit Cleft Palate Associated with Abnormal Tongue Development
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DOI：
10.1074/jbc.m112.432286
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发表时间：
2013-04-12
影响因子：
4.8
通讯作者：
Chen, YiPing
中科院分区：
文献类型：
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作者：
Song, Zhongchen;Liu, Chao;Chen, YiPing
腭裂是人类最常见的先天性出生缺陷之一。转化生长因子β信号转导通路由Smad依赖和Smad非依赖两种途径介导，在调节颅面发育和纹饰方面起着至关重要的作用，尤其是在腭部发育中。然而，目前尚不清楚Smad非依赖性通路是否参与了腭裂形成过程中的转化生长因子β信号转导功能。在这项研究中，我们研究了转化生长因子β活化激酶1(Tak1)的功能，它是Smad非依赖性转化生长因子β信号在腭部发育中的关键调节因子。我们发现Tak1蛋白在发育中的腭突上皮和间充质中均有表达。虽然Tak1在腭裂上皮或间充质中的缺失不会导致腭裂，但在使用WNT1-CRE转基因等位基因的神经脊谱系中Tak1的失活会导致失败的腭隆起和随后的腭裂形成。Wnt1-Cre；Tak1(F/F)小鼠的腭部抬高失败是由于舌头畸形和小颌畸形所致，类似于人类Pierre Robin序列的次级腭裂。我们发现舌发育异常与Fgf10在神经峰舌组织中的过度表达有关。在Fgf10过度表达的小鼠模型中，重现了失败的腭部抬高和腭裂。在发育舌原代细胞培养中，通过抑制Tak1下游的p38，进一步证实了Tak1介导的非规范的转化生长因子β信号对Fgf10表达的抑制作用。因此，Tak1通过控制Fgf10的表达来调控舌体发育，并可能代表人类PrS裂隙突变的候选基因。
Cleft palate represents one of the most common congenital birth defects in humans. TGF beta signaling, which is mediated by Smad-dependent and Smad-independent pathways, plays a crucial role in regulating craniofacial development and patterning, particularly in palate development. However, it remains largely unknown whether the Smad-independent pathway contributes to TGF beta signaling function during palatogenesis. In this study, we investigated the function of TGF beta activated kinase 1 (Tak1), a key regulator of Smad-independent TGF beta signaling in palate development. We show that Tak1 protein is expressed in both the epithelium and mesenchyme of the developing palatal shelves. Whereas deletion of Tak1 in the palatal epithelium or mesenchyme did not give rise to a cleft palate defect, inactivation of Tak1 in the neural crest lineage using the Wnt1-Cre transgenic allele resulted in failed palate elevation and subsequently the cleft palate formation. The failure in palate elevation in Wnt1-Cre; Tak1(F/F) mice results from a malformed tongue and micrognathia, resembling human Pierre Robin sequence cleft of the secondary palate. We found that the abnormal tongue development is associated with Fgf10 overexpression in the neural crest-derived tongue tissue. The failed palate elevation and cleft palate were recapitulated in an Fgf10-overexpressing mouse model. The repressive effect of the Tak1-mediated noncanonical TGF beta signaling on Fgf10 expression was further confirmed by inhibition of p38, a downstream kinase of Tak1, in the primary cell culture of developing tongue. Tak1 thus functions to regulate tongue development by controlling Fgf10 expression and could represent a candidate gene for mutation in human PRS clefting.