Craniofacial Ciliopathies Reveal Specific Requirements for GLI Proteins during Development of the Facial Midline.
Craniofacial Ciliopathies Reveal Specific Requirements for GLI Proteins during Development of the Facial Midline.
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DOI：
10.1371/journal.pgen.1006351
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发表时间：
2016-11
期刊：
影响因子：
4.5
通讯作者：
Brugmann SA
中科院分区：
文献类型：
--
作者：
Chang CF;Chang YT;Millington G;Brugmann SA
纤毛病代表影响多个器官系统的广泛类别的病症。当初级纤毛不起作用时，颅面复合体是受影响最严重的部位之一。我们以前报道，初级纤毛的颅神经嵴细胞的损失，通过条件性敲除鞭毛内转运蛋白KIF 3a，导致面中部扩大由于刺猬（HH）活动的收益。在这里，我们研究了初级纤毛损失如何产生与HH功能获得相关的面部表型的分子机制。我们发现，鞭毛内转运蛋白（KIF 3a或IFFT 88）的损失导致异常GLI处理，使GLI 3FL和GLI 2FL的量增加，从而使GLIFL与GLIR的比例偏向FL亚型。GLI 3R基因的加入部分挽救了纤毛病性面中部增宽。有趣的是，尽管之前的几项研究表明面中部发育严重依赖于GLI 3R活性，但单独GLI 3的条件性丧失并不能重现纤毛病表型。只有GLI 2和GLI 3的联合缺失才能表现出纤毛病的面中部外观。我们的研究结果表明，睫状体病的面部表型是通过GLI 3R和GLI 2 R的丢失产生的，这种病理是通过去抑制机制发生的。此外，这些研究表明GLI 2 R在颅面发育中的新作用。初级纤毛是细胞内普遍存在的细胞器，用于传递分子信号。功能性初级纤毛的丧失导致一类称为纤毛病的疾病。纤毛病具有广泛的表型;然而，严重的面部异常通常与这类疾病相关。面部中线对初级纤毛的丧失特别敏感，经常发生显著的增宽。这种表型与Sonic Hedgehog途径中存在功能获得性缺陷时发生的表型相似。这份手稿地址的分子基础面中部扩大纤毛病变。重要的是，我们确定的机制，以拯救和表型的纤毛病面中部表型。总之，这项工作提供了新的见解面中部图案的分子机制和纤毛的损失影响该过程的程度。
Ciliopathies represent a broad class of disorders that affect multiple organ systems. The craniofacial complex is among those most severely affected when primary cilia are not functional. We previously reported that loss of primary cilia on cranial neural crest cells, via a conditional knockout of the intraflagellar transport protein KIF3a, resulted in midfacial widening due to a gain of Hedgehog (HH) activity. Here, we examine the molecular mechanism of how a loss of primary cilia can produce facial phenotypes associated with a gain of HH function. We show that loss of intraflagellar transport proteins (KIF3a or IFT88) caused aberrant GLI processing such that the amount of GLI3FL and GLI2FL was increased, thus skewing the ratio of GLIFL to GLIR in favor of the FL isoform. Genetic addition of GLI3R partially rescued the ciliopathic midfacial widening. Interestingly, despite several previous studies suggesting midfacial development relies heavily on GLI3R activity, the conditional loss of GLI3 alone did not reproduce the ciliopathic phenotype. Only the combined loss of both GLI2 and GLI3 was able to phenocopy the ciliopathic midfacial appearance. Our findings suggest that ciliopathic facial phenotypes are generated via loss of both GLI3R and GLI2R and that this pathology occurs via a de-repression mechanism. Furthermore, these studies suggest a novel role for GLI2R in craniofacial development. Primary cilia are ubiquitous organelles that serve to transduce molecular signals within a cell. Loss of functional primary cilia results in a disease class called ciliopathies. Ciliopathies have a broad range of phenotypes; however, severe facial anomalies are commonly associated with this disease class. The facial midline is particularly sensitive to loss of primary cilia, frequently undergoing a significant widening. This phenotype is similar to that which occurs when there are gain-of-function defects in the Sonic Hedgehog pathway. This manuscript addresses the molecular basis for midfacial widening in ciliopathies. Importantly, we determine mechanisms to both rescue and phenocopy the ciliopathic midfacial phenotype. In sum, this work provides novel insight into the molecular mechanisms of midfacial patterning and the extent to which loss of cilia impact that process.
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