A primary cilia-dependent etiology for midline facial disorders
A primary cilia-dependent etiology for midline facial disorders
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DOI：
10.1093/hmg/ddq030
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发表时间：
2010-04-15
影响因子：
3.5
通讯作者：
Helms, Jill A.
中科院分区：
文献类型：
--
作者：
Brugmann, Samantha A.;Allen, Nancy C.;Helms, Jill A.
人类的面部表现出巨大的变化。当病理条件叠加在正常的变化，一个几乎完整的一系列面部形态产生。当全面观察时，这个范围从独眼症和距离过短到距离过长和面部重复。Hedgehog通路活性降低导致前脑无裂畸形和距离缩短。在这里，我们表明，过度的刺猬活动，造成截断的初级纤毛对颅神经嵴细胞，导致间距过宽和额鼻发育不良（FND）。消除鞭毛内转运蛋白Kif3a导致面部间充质中的过度刺猬反应，这伴随着Gli1，Ptc和Shh的更广泛的表达结构域，以及Gli3的表达结构域减少。此外，Gli1表达的更广泛的领域对应于Kif3a条件性敲除的面部免疫中神经嵴细胞增殖增强的区域。缺乏初级纤毛的鸟类Talpid胚胎表现出相似的分子变化和相似的面部表型。总的来说，这些数据支持我们的假设，即面部中线的严重狭窄和面部中线的过度扩张都可归因于Hedgehog通路活动的中断。这些数据也提出了编码纤毛蛋白的基因是人类距离过远和FND的候选基因的可能性。
Human faces exhibit enormous variation. When pathological conditions are superimposed on normal variation, a nearly unbroken series of facial morphologies is produced. When viewed in full, this spectrum ranges from cyclopia and hypotelorism to hypertelorism and facial duplications. Decreased Hedgehog pathway activity causes holoprosencephaly and hypotelorism. Here, we show that excessive Hedgehog activity, caused by truncating the primary cilia on cranial neural crest cells, causes hypertelorism and frontonasal dysplasia (FND). Elimination of the intraflagellar transport protein Kif3a leads to excessive Hedgehog responsiveness in facial mesenchyme, which is accompanied by broader expression domains of Gli1, Ptc and Shh, and reduced expression domains of Gli3. Furthermore, broader domains of Gli1 expression correspond to areas of enhanced neural crest cell proliferation in the facial prominences of Kif3a conditional knockouts. Avian Talpid embryos that lack primary cilia exhibit similar molecular changes and similar facial phenotypes. Collectively, these data support our hypothesis that a severe narrowing of the facial midline and excessive expansion of the facial midline are both attributable to disruptions in Hedgehog pathway activity. These data also raise the possibility that genes encoding ciliary proteins are candidates for human conditions of hypertelorism and FNDs.