SATB2 is a schizophrenia risk gene and is genetically associated with human intelligence. How it affects cognition at molecular level is currently unknown. Here, we show that interactions between SATB2, a chromosomal scaffolding protein, and the inner nuclear membrane protein LEMD2 orchestrate the response of pyramidal neurons to neuronal activation. Exposure to novel environment in vivo causes changes in nuclear shape of CA1 hippocampal neurons via a SATB2‐dependent mechanism. The activity‐driven plasticity of the nuclear envelope requires not only SATB2, but also its protein interactor LEMD2 and the ESCRT‐III/VPS4 membrane‐remodeling complex. Furthermore, LEMD2 depletion in cortical neurons, similar to SATB2 ablation, affects neuronal activity‐dependent regulation of multiple rapid and delayed primary response genes. In human genetic data, LEMD2‐regulated genes are enriched for de novo mutations reported in intellectual disability and schizophrenia and are, like SATB2‐regulated genes, enriched for common variants associated with schizophrenia and cognitive function. Hence, interactions between SATB2 and the inner nuclear membrane protein LEMD2 influence gene expression programs in pyramidal neurons that are linked to cognitive ability and psychiatric disorder etiology.

中文翻译：

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SATB2-LEMD2 相互作用将核形状可塑性与认知相关基因的调节联系起来

SATB2是一种精神分裂症风险基因，与人类智力有遗传相关性。目前尚不清楚它如何在分子水平上影响认知。在这里，我们展示了染色体支架蛋白 SATB2 和内核膜蛋白 LEMD2 之间的相互作用协调锥体神经元对神经元激活的反应。暴露于体内新环境会通过 SATB2 依赖性机制导致 CA1 海马神经元的核形状发生变化。核膜的活动驱动的可塑性不仅需要 SATB2，还需要其蛋白质相互作用子 LEMD2 和 ESCRT-III/VPS4 膜重塑复合物。此外，与 SATB2 消融类似，皮质神经元中 LEMD2 的缺失会影响多个快速和延迟初级反应基因的神经元活动依赖性调节。在人类遗传数据中，LEMD2 调控基因富含智力障碍和精神分裂症中报告的从头突变，并且与 SATB2 调控基因一样，富含与精神分裂症和认知功能相关的常见变异。因此，SATB2 和内核膜蛋白 LEMD2 之间的相互作用会影响锥体神经元中与认知能力和精神疾病病因相关的基因表达程序。