Flaherty Erin, Maniatis Tom
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, 10032, United States; Mortimer B. Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, NY, 10027, United States.
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, 10032, United States; Mortimer B. Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, NY, 10027, United States; New York Genome Center, New York, NY 10013, United States.
Curr Opin Genet Dev. 2020 Dec;65:144-150. doi: 10.1016/j.gde.2020.05.041. Epub 2020 Jul 14.
During development, individual neurons extend highly branched arbors that innervate the surrounding territory, enabling the formation of appropriate synaptic connections. The clustered protocadherins (cPCDH), a family of diverse cell-surface homophilic proteins, provide each neuron with a cell specific identity required for distinguishing between self versus non-self. While only 52 unique cPcdh isoforms are encoded in the human genome, a combination of stochastic promoter choice and the formation of a protein lattice through engagement of adjacent cPCDH protein cis/trans-tetramers confer the high degree of cellular specificity required for self-recognition. Studies of mice bearing deletions of individual cPcdh gene clustees have identified deficits in circuit formation and behavior. In humans, single nucleotide variants scattered across the cPCDH locus have been identified, which associate with multiple neurodevelopmental disorders, including autism and schizophrenia. To advance our understanding of cPCDH stochastic choice and maintenance, function across cell types, and contribution to neuropsychiatric disease pathogenesis, hiPSC-based models have been developed. Ultimately, integration of human genetic data, biochemical assays, and functional studies is needed to uncover the mechanism underlying neurite repulsion, which has been implicated in neurodevelopmental disorders.
在发育过程中，单个神经元会延伸出高度分支的树突，支配周围区域，从而形成适当的突触连接。成簇的原钙黏蛋白（cPCDH）是一类多样的细胞表面同嗜性蛋白，为每个神经元提供区分自我与非自我所需的细胞特异性身份。虽然人类基因组中仅编码52种独特的cPcdh异构体，但随机启动子选择以及通过相邻cPCDH蛋白顺式/反式四聚体的结合形成蛋白质晶格，赋予了自我识别所需的高度细胞特异性。对单个cPcdh基因簇缺失的小鼠的研究已经确定了其在神经回路形成和行为方面的缺陷。在人类中，已经鉴定出分布在cPCDH基因座上的单核苷酸变体，这些变体与多种神经发育障碍有关，包括自闭症和精神分裂症。为了增进我们对cPCDH随机选择和维持、跨细胞类型的功能以及对神经精神疾病发病机制的贡献的理解，已经开发了基于人诱导多能干细胞（hiPSC）的模型。最终，需要整合人类遗传数据、生化分析和功能研究，以揭示与神经发育障碍有关的神经突排斥的潜在机制。
