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.

项目总结/文摘