Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development
Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development
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DOI：
10.1073/pnas.1216398109
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发表时间：
2012-10-30
影响因子：
11.1
通讯作者：
Suedhof, Thomas C.
中科院分区：
文献类型：
--
作者：
Anderson, Garret R.;Galfin, Timothy;Suedhof, Thomas C.
编码CASPR2（一种neurexin相关的细胞粘附分子）的接触素相关蛋白2（CNTNAP 2）基因的突变易患自闭症，但CASPR2在神经回路组装中的功能仍然很大程度上未知。在对自闭症候选基因的敲除调查中，我们发现CASPR2是神经网络正常发育所必需的。RNAi介导的CASPR2敲低导致锥体神经元中树突分支和棘发育的细胞自主性减少，导致兴奋性和抑制性突触数量的整体下降以及突触传递的减少，而这些突触的性质没有可检测的变化。我们的数据表明，除了先前描述的CASPR2在成熟神经元中的作用，其中CASPR2组织有髓轴突的节点微区，CASPR2在发育中的神经元中执行早期组织功能，这对于神经回路组装是必不可少的，并且与自闭症谱系障碍（ASD）发病的时间一致。
Mutations in the contactin-associated protein 2 (CNTNAP2) gene encoding CASPR2, a neurexin-related cell-adhesion molecule, predispose to autism, but the function of CASPR2 in neural circuit assembly remains largely unknown. In a knockdown survey of autism candidate genes, we found that CASPR2 is required for normal development of neural networks. RNAi-mediated knockdown of CASPR2 produced a cell-autonomous decrease in dendritic arborization and spine development in pyramidal neurons, leading to a global decline in excitatory and inhibitory synapse numbers and a decrease in synaptic transmission without a detectable change in the properties of these synapses. Our data suggest that in addition to the previously described role of CASPR2 in mature neurons, where CASPR2 organizes nodal microdomains of myelinated axons, CASPR2 performs an earlier organizational function in developing neurons that is essential for neural circuit assembly and operates coincident with the time of autism spectrum disorder (ASD) pathogenesis.