神经管畸形是一组基因型和表型高度异质性的出生缺陷，致病基因不明。PCP、Shh信号通路在神经管的形成过程中发挥着重要作用。纤毛作为PCP、Shh信号通路中关键元素调节参与了神经管的发育过程。纤毛蛋白功能障碍将导致中枢神经系统等多系统发育异常，NTDs是最常见的表型之一。我们前期研究发现纤毛基因变异和人类NTDs相关，且在人颅NTDs中发现导致MKS1基因表达终止的2个移码突变。本项目研究验证MKS1基因移码突变与人颅部NTDs发生的相关性，利用小鼠胚胎成纤维细胞研究MKS1基因移码突变后Shh、PCP通路核心蛋白的表达水平、分布以及纤毛的形成。利用RNAi 技术建立MKS1基因沉默的鸡胚模型，分析鸡神经发育表型，研究MKS1沉默后Shh、PCP核心蛋白在鸡胚神经上皮细胞表达、定位及纤毛的变化情况。

Neural tube defects (NTDs) are a group of birth defects with highly genotypic and phenotypic heterogeneity. Their pathogenic genes remain unknown. Shh and pcp signaling pathway play an important role in the development of neural tube. It is now clear that primary cilia have a crucial role as a specialized compartment for extracellular signal transduction that responds to sonic Hedgehog (Hh) and pcp signaling pathway. Cilia dysfunction will result in multiple systemic dysfunction, including NTDs as one of the most common phenotypes. Our previous studies have showed that variants in cilia gene are related to human NTDs. Particularly, two frameshift mutations of MKS1 gene creating stop code have been identified in human cranial NTD. We will study the protein binding, expression and localization of core Shh or PCP proteins in MKS1 knock-down MEF cell. we will explore the developmental phenotypes of chick embryo and the localization, expression of core Shh or PCP proteins in neurepithelium in MKS1 knocked-down chick embryo model ...