Using the avian mutant talpid2 as a disease model for understanding the oral-facial phenotypes of oral-facial-digital syndrome.
Using the avian mutant talpid2 as a disease model for understanding the oral-facial phenotypes of oral-facial-digital syndrome.
复制标题
使用禽类突变体 talpid2 作为疾病模型来了解口腔-面部-数字综合征的口腔-面部表型。
DOI：
10.1242/dmm.020222
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发表时间：
2015-08-01
影响因子：
4.3
通讯作者：
Brugmann SA
中科院分区：
文献类型：
--
作者：
Schock EN;Chang CF;Struve JN;Chang YT;Chang J;Delany ME;Brugmann SA
口-面-指综合征（oral-facial-digital syndrome，OFD）是一种以口-面异常为特征的纤毛病变，包括唇腭裂、宽鼻根、牙齿异常、小颌畸形和舌缺损。此外，这些个体还具有其他几种纤毛病变的典型特征性异常，包括多指（趾）畸形、多囊性肾和小脑发育不全。最近，人类OFD病例的一个子集已被链接到中心粒蛋白C2钙依赖性结构域3（C2CD 3）的突变。我们以前的工作确定C2CD 3突变为禽talpid 2突变体的致病性遗传病变。基于这种常见的遗传病因，我们重新检查了talpid 2突变体的生化和表型特征的OFD。我们发现，在OFD受影响的个体中，C2CD 3和口-面-指综合征1蛋白（OFD 1）之间的蛋白质-蛋白质相互作用在talpid 2细胞中减少。此外，我们发现，所有常见的表型之间的OFD影响的个人和鸟类talpid 2突变体是保守的。鉴于这些发现，我们利用talpid 2模型来研究OFD中存在的口面部表型的细胞基础。具体而言，我们研究了颅神经嵴细胞（CNCC）的发展和分化时，C2CD 3依赖的纤毛受损。我们的研究表明，虽然C2CD 3依赖的纤毛发生中断不影响CNCC的规范或增殖，CNCC迁移和分化被破坏。C2CD 3依赖性纤毛发生的丧失影响了迁移性CNCC的分散和定向持久性。此外，C2CD 3依赖的纤毛发生的损失导致畸形和扩大CNCC衍生的面部软骨。因此，这些研究结果表明，异常CNCC迁移和分化可能有助于OFD口面部缺损的病理学。总结：本研究利用一种天然存在的鸟类突变体talpid 2来确定口-面-指综合征中存在的口-面表型的细胞基础。
Oral-facial-digital syndrome (OFD) is a ciliopathy that is characterized by oral-facial abnormalities, including cleft lip and/or palate, broad nasal root, dental anomalies, micrognathia and glossal defects. In addition, these individuals have several other characteristic abnormalities that are typical of a ciliopathy, including polysyndactyly, polycystic kidneys and hypoplasia of the cerebellum. Recently, a subset of OFD cases in humans has been linked to mutations in the centriolar protein C2 Ca2+-dependent domain-containing 3 (C2CD3). Our previous work identified mutations in C2CD3 as the causal genetic lesion for the avian talpid2 mutant. Based on this common genetic etiology, we re-examined the talpid2 mutant biochemically and phenotypically for characteristics of OFD. We found that, as in OFD-affected individuals, protein-protein interactions between C2CD3 and oral-facial-digital syndrome 1 protein (OFD1) are reduced in talpid2 cells. Furthermore, we found that all common phenotypes were conserved between OFD-affected individuals and avian talpid2 mutants. In light of these findings, we utilized the talpid2 model to examine the cellular basis for the oral-facial phenotypes present in OFD. Specifically, we examined the development and differentiation of cranial neural crest cells (CNCCs) when C2CD3-dependent ciliogenesis was impaired. Our studies suggest that although disruptions of C2CD3-dependent ciliogenesis do not affect CNCC specification or proliferation, CNCC migration and differentiation are disrupted. Loss of C2CD3-dependent ciliogenesis affects the dispersion and directional persistence of migratory CNCCs. Furthermore, loss of C2CD3-dependent ciliogenesis results in dysmorphic and enlarged CNCC-derived facial cartilages. Thus, these findings suggest that aberrant CNCC migration and differentiation could contribute to the pathology of oral-facial defects in OFD. Summary: This study utilizes a naturally occurring avian mutant known as talpid2 to determine the cellular basis for the oral-facial phenotypes present in oral-facial-digital syndrome.