CSDE1基因组转录后调控及其在神经发育和孤独症发生中的作用机制研究

Autism is a group of neurodevelopmental disorders. The global incidence has reached as high as 1%. Previously, we found that variants of RNA-binding protein CSDE1 are associated with autism risk and disease-associated variants affect the expression level of CSDE1. Other studies also found de novo mutation and copy number variations of CSDE1 in autism patients and interference of CSDE1 in mice affect neuronal migration. We further found that CSDE1 coexpressed with multiple autism risk genes, and that CSDE1 participates in the mTOR signaling pathway and affects the expression of downstream autism-risk genes. Next, we constructed the heterozygous CSDE1 knockout mice and found that it showed depressive behavior. We further constructed the brain-conditional knockout mice. Based on these identifications and progress, this project proposes to elucidate the genomic regulation mechanisms of CSDE1 and its role in neurodevelopment and autism pathogenesis from the following aspects: 1. Identifying genome-wide RNA targets of CSDE1 and the RNA-binding mechanism; 2. post-transcriptional regulation mechanisms of CSDE1; 3. identifying the neurodevelopmental behaviors of conditional knockout mice; 4. morphological and physiological phenotypes of CSDE1 conditional knockout mice and its role in the neural developmental processes and autism pathogenesis.

孤独症是严重影响儿童健康的神经发育疾病，全球发病率高达1%。前期GWAS研究我们发现RNA结合蛋白CSDE1变异与孤独症发病相关且影响其表达水平。其他研究也发现CSDE1新发突变和CNV参与孤独症发生且干扰CSDE1影响神经元迁移。进一步我们发现CSDE1与多个孤独症基因共表达；参与mTOR通路并影响下游孤独症基因表达；CSDE1杂合敲除小鼠表现抑郁行为；另外我们又构建了条件敲除小鼠。基于以上基础我们提出假设：CSDE1通过结合RNA进行基因转录后调控从而影响神经发育和孤独症发生。针对该假设，本项目拟开展以下研究：1. CSDE1在基因组水平结合的RNA及结合RNA的机制；2. CSDE1基因组转录后调控机制；3.条件敲除小鼠的行为学表现；4. CSDE1神经发育相关形态和生理表型及参与神经发育的分子机制。项目对阐明CSDE1转录后调控机制及其参与神经发育和孤独症发生的机制具有重要意义。

孤独症是严重影响儿童健康的神经发育疾病，全球发病率高达1%。我们的前期研究发现 RNA结合蛋白编码基因CSDE1的常见变异与孤独症发病风险相关。本项目在前期研究的基础上对CSDE1参与孤独症风险以及神经发育的机制进行进一步研究。主要研究结果如下：1）鉴定一个由 CSDE1功能缺失突变导致孤独症分子亚型；2）从全基因组水平系统解析了CSDE1结合的目标RNA，并发现CSDE1结合靶标主要富集在孤独症及神经发育相关基因；3）CSDE1可能通过调控Wnt信号通路参与神经元发育，包括轴突生长，树突复杂度以及树突棘的发育等；4）CSDE1维持突触传递稳态，功能缺失导致突触传递异常；5）CSDE1可能通过调控细胞周期参与神经干细胞的增殖；6）CSDE1参与早期脑发育的神经元迁移。本项目顺利完成了预期研究内容，达到预期目标，研究结果为CSDE1参与孤独症发生的遗传机制和参与神经发育和功能的分子机制提供理论数据，为未来开发CSDE1分子亚型患者的干预和治疗提供科学依据。