Neural crest-specific deletion of Rbfox2 in mice leads to craniofacial abnormalities including cleft palate
Neural crest-specific deletion of Rbfox2 in mice leads to craniofacial abnormalities including cleft palate
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DOI：
10.7554/elife.45418
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发表时间：
2019-06-26
期刊：
影响因子：
7.7
通讯作者：
Singh, Manvendra K.
中科院分区：
文献类型：
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作者：
Cibi, Dasan Mary;Mia, Masum M.;Singh, Manvendra K.
选择性剪接（AS）通过从单个蛋白质编码基因产生大量转录本，从有限大小的基因组中产生蛋白质组多样性。AS的组织特异性调节因子是基因调控网络的重要组成部分，是正常细胞功能、组织形成和胚胎发育所必需的。然而，它们在神经嵴发育中的细胞自主功能尚未被探索。在这里，我们表明，剪接因子Rbfox 2在神经嵴细胞（NCCs）中表达，缺失Rbfox 2在NCCs导致腭裂和颅面骨发育缺陷。RNA-Seq分析显示，Rbfox 2调节神经嵴/颅面发育所必需的许多基因的剪接和表达。我们证明，Rbfox 2-TGF-β-Tak 1信号转导轴是由Rbfox 2缺失失调。此外，通过Tak 1过表达恢复TGF-β信号传导可以挽救Rbfox 2突变体中观察到的增殖缺陷。我们还确定了一个正反馈回路，其中TGF-β信号促进NCC中Rbfox 2的表达。
Alternative splicing (AS) creates proteomic diversity from a limited size genome by generating numerous transcripts from a single protein-coding gene. Tissue-specific regulators of AS are essential components of the gene regulatory network, required for normal cellular function, tissue patterning, and embryonic development. However, their cell-autonomous function in neural crest development has not been explored. Here, we demonstrate that splicing factor Rbfox2 is expressed in the neural crest cells (NCCs), and deletion of Rbfox2 in NCCs leads to cleft palate and defects in craniofacial bone development. RNA-Seq analysis revealed that Rbfox2 regulates splicing and expression of numerous genes essential for neural crest/craniofacial development. We demonstrate that Rbfox2-TGF-beta-Tak1 signaling axis is deregulated by Rbfox2 deletion. Furthermore, restoration of TGF-beta signaling by Tak1 overexpression can rescue the proliferation defect seen in Rbfox2 mutants. We also identified a positive feedback loop in which TGF-beta signaling promotes expression of Rbfox2 in NCCs.