大脑皮层发育异常是常见的出生缺陷，是引起儿童发育障碍疾病如原发性小头畸形的主要原因。探究其发生机制是神经科学、胚胎学、儿科学等交叉学科的关键科学问题。神经干细胞（NSCs）的增殖分化、迁移成熟是脑发育的细胞学基础，从NSCs层面探讨大脑发育性疾病的发病机制是研究的突破点。TOX3是含HMG-box结构域的转录因子。本课题首次构建TOX3基因敲除小鼠，表现出类似于小头畸形的表型：脑体积减小，大脑皮层变薄且结构紊乱，NSCs增殖分化减少。本研究拟在前期基础上，利用免疫组化、透射电镜、ChIP-seq等技术，探讨TOX3在大脑皮层发育中的作用及调控机制，初步构建TOX3与表观遗传因子的调控网络，并结合行为学分析TOX3在智力情绪方面的作用及机制。本课题构建了基因敲除小鼠动物模型，从调控NSCs层面探究TOX3对大脑皮层发育的影响，并为小头畸形等大脑发育疾病的临床治疗提供研究基础和理论依据。

Abnormal development of the cerebral cortex is a common developmental disorder of children，such as primary microcephaly. Studying the mechanisms of neurodevelopmental disorders is the key scientific question of neuroscience, embryology, pediatrics, etc.The proliferation, differentiation, migration and maturation of the neural stem cells (NSCs) is the cellular basis of brain development, and moreover, the abnormal regulation of neural stem cell may be related to the pathogenesis of neurodevelopmental disorders. TOX3 is a transcription factor containing a high mobility group (HMG)-box domain. Our preliminary data demonstrated that TOX3 knockout mouse showed many microcephaly phenotypes: a reduced brain size, a thinned cerebral cortex and neuronal disorganization without normal six cortical layers, which may be due to decreased proliferation and differentiation of NSCs. On the basis of above findings, we will determine the role of TOX3 in the development of cerebral cortex and the mechanism through which TOX3 contributes to NSCs by using immunofluorescence, TEM and ChIP-seq, etc. We will establish a network of gene regulation in NSCs in genetic and epigenetic levels and analysis the roles and mechanisms of TOX3 in learning and emotion using animal behavioral model. This study creates a gene knockout mouse model and explores the pathogenic mechanisms of cortial development from the regulation of NSCs, thereby sheds light on the future strategies for therapeutic targeting for neurodevelopmental disorders.