Mechanisms by Which Macrocephaly Underlies Autism Spectrum Disorder

自闭症谱系障碍中大头畸形的机制

• 批准号: 10593343
• 负责人: BYOUNG-IL BAE
• 金额: $ 24.63万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593343
• 关键词: ARHGEF5 gene; ASD patient; Address; Adult; Affect; Behavior; Behavioral Assay; Brain; CTNNB1 gene; Cell Aging; Cell Cycle; Cell Death; Cell Proliferation; Cells; Centrosome; Cerebral cortex; Child; Cognitive; Cultured Cells; DLG4 gene; Data; Development; Embryo; FOS gene; Functional disorder; Gene Abnormality; Genes; Genetic; Goals; Heritability; Human; Immediate-Early Genes; In Situ Hybridization; Knock-in; Knock-in Mouse; Language; Macrocephaly; Mammals; Medial; Mediating; Microcephaly; Missense Mutation; Mus; Mutation; Neurodevelopmental Disorder; Neuroepithelial Cells; Neuroglia; Neuronal Differentiation; Neurons; PTEN gene; PTPNS1 gene; Patients; Perinatal; Prefrontal Cortex; Proliferating; Proteins; Radial; Research; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Social Behavior; Social Controls; Symptoms; Synapses; Techniques; Testing; Undifferentiated; Variant; Weight; autism spectrum disorder; beta catenin; boys; brain size; cell type; de novo mutation; early childhood; gain of function; gain of function mutation; gene product; innovation; loss of function mutation; male; mouse model; neurogenesis; novel; novel therapeutic intervention; postnatal; progenitor; risk variant; single nucleus RNA-sequencing; social; social cognition

PROJECT SUMMARY/ABSTRACT Autism spectrum disorder (ASD) is a highly heritable, heterogeneous neurodevelopmental disorder affecting 1 in 53 children in the US. The prefrontal cortex, which mediates social cognition and language, is oddly enlarged in at least 15% of patients with ASD who suffer from severe symptoms. Macrocephaly (large brain) is caused by excessive proliferation of cortical progenitors, and progenitors derived from ASD patients show excessive proliferation. However, the extent to which prefrontal macrocephaly itself contributes to the pathophysiology of ASD is unclear. ASPM (abnormal spindle-like microcephaly-associated) is a neurodevelopmental gene that determines cortical size, and may play a role in macrocephaly, as well as in ASD. ASPM controls cell proliferation, and its loss-of-function mutations are the most common cause of genetic microcephaly (small brain) that are particularly severe in the prefrontal cortex. Importantly, it is expressed in cortical progenitors but not in neurons. Recently, de novo variants in ASPM have been associated with ASD. Our preliminary data show that one such variant increases ASPM protein levels in cultured cells, suggesting gain-of-function mutation. Furthermore, we generated Aspm knock-in mice with the gain-of-function mutation, which show excessive neurogenesis, perinatal macrocephaly, and abnormal social behavior recapitulating ASD-like symptoms. Our long-term goal is to understand the mechanisms by which abnormal cerebral cortical development underlies functional abnormalities in ASD. Our central hypothesis is that excessive embryonic neurogenesis, which results in macrocephaly, is sufficient to elicit some ASD-like behaviors by disturbing cell signaling and composition in the postnatal brain. To test the hypothesis, we will leverage the ASD-associated gain-of-function mutation in ASPM, and examine Aspm knock-in mice in three Specific Aims. Thus, we will (Aim 1) investigate the neurodevelopmental trajectory using immunostaining, (Aim 2) determine changes in cell composition and signaling using single-nucleus RNA sequencing, (Aim 3) social cognitive behaviors in Aspm knock-in mice. Our proposed research is significant as we directly address the pathophysiological role of macrocephaly in ASD. It is innovative as we analyze a novel ASD mouse model with a gain-of-function mutation in the neurodevelopmental gene ASPM using diverse, state-of-the-art techniques. Macrocephaly is observed in some ASD patients with severe symptoms. However, the extent to which macrocephaly itself contributes to ASD is unclear. Our novel Aspm knock-in mice carry an ASD-associated mutation and display perinatal macrocephaly with abnormal social behavior. Exploring dysregulated cell types and signaling pathways in Aspm knock-in mice may provide novel therapeutic interventions for ASD.

项目概要/摘要 自闭症谱系障碍 (ASD) 是一种高度遗传的异质性神经发育障碍 影响美国五分之一的儿童。奇怪的是，负责调节社会认知和语言的前额叶皮层 至少 15% 患有严重症状的自闭症谱系障碍 (ASD) 患者中，这种情况会出现扩大。巨头畸形（大大脑）是 由皮质祖细胞过度增殖引起，来自 ASD 患者的祖细胞显示 过度增殖。然而，前额叶巨头畸形本身在多大程度上导致了 ASD 的病理生理学尚不清楚。 ASPM（异常纺锤样小头畸形相关）是一种神经发育基因，决定 皮质大小，可能在大头畸形和自闭症谱系障碍中发挥作用。 ASPM 控制细胞增殖，其 功能丧失突变是遗传性小头畸形（小脑）的最常见原因，尤其是 严重的是前额皮质。重要的是，它在皮质祖细胞中表达，但在神经元中不表达。最近， ASPM 的从头变异与自闭症谱系障碍 (ASD) 相关。我们的初步数据表明，这样的一种变体 增加培养细胞中的 ASPM 蛋白水平，表明功能获得性突变。此外，我们 产生了具有功能获得性突变的 Aspm 敲入小鼠，显示出过度的神经发生、围产期 巨头畸形和异常的社会行为，重现自闭症谱系障碍（ASD）样症状。 我们的长期目标是了解大脑皮层发育异常的机制 是 ASD 功能异常的基础。我们的中心假设是过度的胚胎神经发生， 这会导致巨头畸形，足以通过干扰细胞信号传导和引发一些类似自闭症谱系障碍的行为 出生后大脑的组成。为了检验这个假设，我们将利用 ASD 相关的功能增益 ASPM 突变，并在三个特定目标中检查 Aspm 敲入小鼠。因此，我们将（目标 1）调查 使用免疫染色的神经发育轨迹，（目标 2）确定细胞组成的变化和 使用单核 RNA 测序进行信号传导，（目标 3）Aspm 敲入小鼠的社会认知行为。我们的 拟议的研究意义重大，因为我们直接解决了自闭症谱系障碍中大头畸形的病理生理学作用。它 具有创新性，因为我们分析了一种新型 ASD 小鼠模型，该模型具有功能获得性突变 神经发育基因 ASPM 使用多种最先进的技术。 在一些症状严重的 ASD 患者中观察到大头畸形。然而，在多大程度上 巨头畸形本身是否会导致 ASD 尚不清楚。我们的新型 Aspm 敲入小鼠携带 ASD 相关基因 突变并表现出围产期大头畸形和异常社会行为。探索失调的细胞类型 Aspm 敲入小鼠中的信号通路可能为 ASD 提供新的治疗干预措施。