大脑皮层功能区域的正常形成（图式形成）是脑认知功能的关键结构基础。部分自闭症患者具有组蛋白H3第36位赖氨酸甲基化酶SETD2和NSD1的失活突变，但因果关系和分子机制尚不清楚。前期研究发现在发育中小鼠大脑皮层敲除Setd2导致大脑皮层额叶和运动区向后扩展，体感皮层向后、向内压缩；Setd2敲除小鼠具有显著的社交障碍、空间记忆障碍和神经投射异常，决定大脑皮层图示形成和神经环路建立的关键分子的表达发生显著改变。拟开展下列研究：确定敲除Nsd1后大脑皮层功能区域和投射的具体变化以及行为学改变；研究SETD2和NSD1是在神经前体细胞水平还是在神经元水平调控大脑皮层图式和神经环路形成；综合应用表观遗传学技术明确SETD2和NSD1的下游靶基因以及调控机制。本研究不但首次鉴定组蛋白甲基转移酶在大脑皮层图示形成中的关键作用和相关机制，并能加深对发育相关神经系统疾病，如先天智力障碍和自闭症发生的认识。

The formation of functional regions of the cerebral cortex (area patterning) lays the foundation of normal brain cognitive function. Loss-of-function mutations of SETD2 and NSD1, two methyltransferases for methylation of the lysine 36 of histone H3, were identified in some patients with autism spectrum disorder (ASD). However, the definitive causal effects and molecular mechanisms by them are elusive. We found conditional ablation of Setd2 in embryonic cortices leads to prominent caudal expansion of the frontal/motor region at the expense of normal localization of the sensory cortex. Moreover, Setd2 conditional knockout mice display prominent defects in social interaction, space memory and cortico-thalamic projections, as well as aberrant expressions of molecules required for area patterning and neural circuitry formation. In this proposal, we will study in detail the neurological and behavioral phenotypes caused by Setd2 or Nsd1 depletion and the underlying molecular mechanisms: 1) Describe the area patterning, axonal projection alterations and social behavioral defects of Nsd1 conditional knockout mice; 2) Determine if SETD2 and NSD1 regulate area patterning of neocortex by affecting neural progenitor cells and/or cortical projection neurons; 3) Dissect SETD2 and NSD1's essential downstream target genes and regulatory mechanisms using biochemical and epigenetic means. Fulfilling the project will not only unveil novel roles and mechanisms of histone methyltransferases in cortical development, but also have implications in understanding pathogenesis of development-related neurological diseases including intellectual disability and ASD.