Intraflagellar transport 88 (IFT88) is crucial for craniofacial development in mice and is a candidate gene for human cleft lip and palate
Intraflagellar transport 88 (IFT88) is crucial for craniofacial development in mice and is a candidate gene for human cleft lip and palate
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DOI：
10.1093/hmg/ddx002
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发表时间：
2017-03-01
影响因子：
3.5
通讯作者：
Chai, Yang
中科院分区：
文献类型：
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作者：
Tian, Hua;Feng, Jifan;Chai, Yang
纤毛病是由初级纤毛缺陷引起的多效性人类疾病，这些患者常伴有唇腭裂。IFT88对初级纤毛的组装和功能是必需的，初级纤毛介导关键的发育信号通路的活性。通过对一个有三名患有单纯唇腭裂的患病兄弟姐妹的家庭进行全外显子组测序，我们发现他们在IFT88中共享一个新的错义突变（c.915G>C，p.E305D），这表明该基因应被视为单纯口面裂的一个候选基因。为了评估IFT88在调节颅面发育中的功能，我们构建了Wnt1 - Cre；Ift88(fl/fl)小鼠，以特异性地在颅神经嵴（CNC）细胞中敲除Ift88。Wnt1 - Cre；Ift88(fl/fl)幼崽由于严重的颅面缺陷，包括双侧唇腭裂和无舌，在出生时死亡，这是由于CNC衍生的腭间充质中的初级纤毛缺失所致。Ift88的缺失还导致在腭形成的早期阶段神经嵴细胞增殖减少以及腭间充质中Shh信号通路的下调。重要的是，Osr2KI - Cre；Ift88(fl/fl)小鼠，其中Ift88在腭间充质中特异性缺失，表现出单纯腭裂。综上所述，我们的结果表明，IFT88在小鼠唇腭区域的CNC衍生间充质的初级纤毛内具有高度保守的功能，并且是人类口面裂基因的一个强有力的候选基因。
Ciliopathies are pleiotropic human diseases resulting from defects of the primary cilium, and these patients often have cleft lip and palate. IFT88 is required for the assembly and function of the primary cilia, which mediate the activity of key developmental signaling pathways. Through whole exome sequencing of a family of three affected siblings with isolated cleft lip and palate, we discovered that they share a novel missense mutation in IFT88 (c. 915G> C, p. E305D), suggesting this gene should be considered a candidate for isolated orofacial clefting. In order to evaluate the function of IFT88 in regulating craniofacial development, we generated Wnt1-Cre; Ift88(fl/fl) mice to eliminate Ift88 specifically in cranial neural crest (CNC) cells. Wnt1-Cre; Ift88(fl/fl) pups died at birth due to severe craniofacial defects including bilateral cleft lip and palate and tongue agenesis, following the loss of the primary cilia in the CNC-derived palatal mesenchyme. Loss of Ift88 also resulted in a decrease in neural crest cell proliferation during early stages of palatogenesis as well as a downregulation of the Shh signaling pathway in the palatal mesenchyme. Importantly, Osr2KI-Cre; Ift88(fl/fl) mice, in which Ift88 is lost specifically in the palatal mesenchyme, exhibit isolated cleft palate. Taken together, our results demonstrate that IFT88 has a highly conserved function within the primary cilia of the CNC-derived mesenchyme in the lip and palate region in mice and is a strong candidate as an orofacial clefting gene in humans.