Menin-FoxG1的调控机制及其与自闭症谱系障碍的关系

自闭症谱系障碍是严重威胁儿童成长的精神疾病，其中遗传变异是导致自闭症的主要因素。但目前对这些基因表达的调控机制仍不清楚。我们发现基因11q13.1的微片段缺失与自闭症密切相关，其中一个基因MEN1（蛋白为menin）引起了我们的关注。Menin具有调控神经发育的作用，但其是否参与了自闭的发展仍不清楚。我们构建了神经元特异敲除Men1的小鼠，发现此小鼠表现出强烈的自闭样行为。通过多组学筛选，我们推测menin有可能结合ATRX蛋白来调控FoxG1的表达。而menin缺失会导致FoxG1表达下调，导致小鼠自闭样行为。为了验证这一假说，我们将基于多种Men1神经系统条件性敲除小鼠，结合多实验手段，详细阐述兴奋性神经元内menin的缺失造成的FoxG1表达异常与自闭症的关系及其上下游的机制。该研究有助于深入理解自闭症核心症状发生的基因调控基础，为自闭症的诊疗提供理论基础和新的药物调控靶点。

Autism spectrum disorder is a mental illness that seriously threatens the growth of children, in which genetic variation is the main factor leading to autism。But the regulatory mechanism of these gene expressions is still unclear. We found that the micro-fragment deletion of gene 11q13.1 is closely related to autism, and one of the genes MEN1 (the protein is menin) has attracted our attention. Menin can regulate neurodevelopment, but whether it is involved in the development of autism is still unknown. We constructed a excitatory neuron-specific mice that knocked out Men1 and found that this mouse exhibited strong autistic behaviors. Through multi-omics screening, we speculated that menin may bind ATRX protein to regulate the expression of FoxG1. The lack of menin can lead to down-regulation of FoxG1 expression, leading to autistic behavior in mice. In order to verify this hypothesis, Based on a variety of menin nervous system conditional knockout mice and combined with multiple experimental methods, we will elaborate on the relationship between the abnormal expression of FoxG1 caused by the lack of menin in excitatory neurons and autism, as well as its upstream and downstream mechanisms.This research is helpful to deeply understand the gene regulation basis of the core symptoms of autism, and provides a theoretical basis and new drug regulation targets for the diagnosis and treatment of autism.