MYCN突变导致精神发育迟滞的分子机制研究

Mental retardation can lead to human disability, and genetic factors may be important to the disease. We found five cases carrying MYCN missense mutation among children with mental retardation; overexpression of MYCN strongly promoted axonal growth. MYCN gene may be a candidate gene resulting in abnormal neurodevelopment, but its role in neuronal development is unclear. We found that MYCN influenced the expression level of Phosphatase and Tensin Homolog (PTEN). Therefore, in this study, we will:1. examine the role of mutation of MYCN in brain development by measuring the neuronal morphology of primary mouse cortical neurons; 2. examine the role of mutation of MYCN in brain structure and neural migration by utero electroporation; 3. explore the mechanism of MYCN gene signaling pathways by using ChIPseq, RNAseq analysis. This study can clarify the mechanism of MYCN gene in neurological development.

精神发育迟滞是导致人类残疾的重要原因之一，遗传因素可能是其重要致病机制。课题组对精神发育迟滞的508患儿进行了全外显子组测序，共发现五例MYCN基因致病突变，且MYCN过表达可促进神经元轴突生长，提示MYCN基因是影响神经发育的候选基因,但其具体作用机制尚不明确。前期发现MYCN基因影响PI3K/AKT/mTOR信号通路中PTEN基因表达水平。因此，本课题拟：（1）体外神经元培养进一步探究MYCN突变体对神经元发育影响；（2）采用在体胚胎电转技术，观察MYCN基因突变对小鼠大脑皮层发育及神经元迁移的影响；（3）应用ChIPseq、RNAseq等手段进一步研究MYCN互作蛋白，信号通路及调控神经发育的靶基因，并观察MYCN 基因突变体对相关信号通路及其调控靶基因的影响。以期阐明MYCN基因突变影响神经元发育的分子机制。

精神发育迟滞是导致人类残疾的重要原因之一，遗传因素可能是其重要致病机制。本课题组对精神发育迟滞的508患儿进行了全外显子组测序，共发现五例MYCN基因致病突变，且MYCN过表达可促进神经元轴突生长，提示MYCN基因是影响神经发育的候选基因,但其具体作用机制尚不明确。前期发现MYCN基因影响PI3K/AKT/mTOR信号通路中PTEN基因表达水平。因此，本课题进一步通过（1）体外神经元培养进一步探究MYCN突变体对神经元发育影响；（2）采用在体胚胎电转技术，观察MYCN基因突变对小鼠大脑皮层发育及神经元迁移的影响； （3）应用ChIPseq、RNAseq等手段进一步研究MYCN互作蛋白，信号通路及调控神经发育的靶基因，并观察MYCN 基因突变体对相关信号通路及其调控靶基因的影响，已进一步阐明MYCN基因突变影响神经元发育的分子机制。