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.

项目摘要/摘要 自闭症谱系障碍（ASD）是一种高度可遗传的，异质的神经发育障碍 在美国影响53名儿童中有1个。介导社会认知和语言的前额叶皮层是奇怪的 至少有15％患有严重症状的ASD患者中，至少有15％的人扩大。大脑（大脑）是 由皮质祖细胞的过度增殖和衍生自ASD患者的祖细胞引起的 过度增殖。但是，前额叶脑畸形本身在多大程度上有助于 ASD的病理生理尚不清楚。 ASPM（异常纺锤样小头畸形相关）是一种神经发育基因，它决定 皮质大小，并且可能在脑畸形以及ASD中发挥作用。 ASPM控制细胞增殖及其 功能丧失突变是遗传小头畸形（小脑）的最常见原因，特别是 前额叶皮层严重。重要的是，它在皮质祖细胞中表示，但在神经元中不表达。最近， ASPM中的从头变体与ASD相关联。我们的初步数据表明一个这样的变体 增加了培养细胞中的ASPM蛋白水平，表明功能性突变。此外，我们 产生的ASPM敲入小鼠具有功能收益突变，该突变表现出过多的神经发生，围产期 脑畸形和异常的社会行为概括了类似ASD的症状。 我们的长期目标是了解异常脑皮质发育的机制 ASD的功能异常。我们的中心假设是过多的胚胎神经发生， 这会导致脑畸形，足以通过干扰细胞信号传导和 产后大脑中的组成。为了检验假设，我们将利用与ASD相关的功能获得 ASPM中的突变，并检查三个特定目的的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，（AIM 2）确定细胞组成的变化和 使用单核RNA测序的信号传导（AIM 3）ASPM敲入小鼠中的社会认知行为。我们的 拟议的研究很重要，因为我们直接解决了脑头畸形在ASD中的病理生理作用。它 当我们分析具有功能获得突变的新型ASD小鼠模型时，具有创新性 使用多样化的最先进技术的神经发育基因ASPM。 在某些患有严重症状的ASD患者中观察到大畸形。但是，在多大程度上 脑畸形本身对ASD的贡献尚不清楚。我们的小说ASPM敲入小鼠携带ASD相关的 突变和表现出异常社会行为的围产期宏观畸形。探索失调的细胞类型 ASPM敲入小鼠中的信号通路可能会为ASD提供新的治疗干预措施。