Autism-specific mutation in DACT1: Impact on brain development in a mouse model

DACT1 中自闭症特异性突变：对小鼠模型大脑发育的影响

• 批准号: 7862322
• 负责人: Benjamin N.R. Cheyette
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-08 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7862322
• 关键词: Address; Affect; Affinity; Amino Acids; Animal Model; Area; Autistic Disorder; Basic Science; Behavior; Behavior Disorders; Binding; Biochemical; Biological; Biological Models; Brain; Child; Complex; Development; Diagnosis; Dimerization; Disease; Electrophysiology (science); Engineering; Family; Funding; Gene Mutation; Generations; Genetic Predisposition to Disease; Goals; Grant; Hippocampus (Brain); Human; In Vitro; Individual; Inhibitory Synapse; Intention; Knock-in Mouse; Knockout Mice; Laboratories; Lead; Link; Methods; Morphology; Mutation; National Institute of Mental Health; Neurites; Neurons; Pathogenesis; Phenotype; Physiology; Positioning Attribute; Post-Translational Protein Processing; Property; Prosencephalon; Proteins; Psychiatrist; Psychiatry; Reading; Research; Research Personnel; Role; Scientist; Signal Transduction; Single Nucleotide Polymorphism; Slice; Societies; System; Tertiary Protein Structure; Training; United States; Variant; Vertebral column; autism spectrum disorder; base; career; cell type; design; genetic pedigree; improved; mouse model; neurodevelopment; novel; postnatal; protein function; public health priorities; public health relevance; research study; success; synaptogenesis

DESCRIPTION (provided by applicant): We have identified a novel single nucleotide polymorphism (SNP) in the DACT1 locus that alters an evolutionarily conserved amino acid in a conserved domain of the protein. We hypothesize that this SNP, which tracks with the diagnosis of autism in an affected family, alters protein function in developing neurons to cause the disease. We have developed a model system in which to study functions of the corresponding protein in early postnatal forebrain neurons, a cell type that is likely to be relevant to autism pathogenesis. This system uses a novel conditional knock-out mouse line generated in my laboratory together with established methods for studying the maturation of hippocampal neurons (HCNs) in culture. Our specific aims are to answer the following questions: 1. Does loss of Dact1 have developmental consequences in forebrain neurons? 2. Does the autism-variant Dact1 protein have different biochemical properties than the wild type Dact1 protein? 3. Do the wild type and autism-variant Dact1 proteins display functional differences during neural development? This is an exploratory grant to the National Institute of Mental Health to support the laboratory of a young investigator who is a psychiatrist trained as a basic scientist. Our goal is to rapidly exploit this opportunity to investigate functions of a wild type and an autism-linked variant Dact1 protein during neural development. It is hoped that this will lead to a major area of research in this laboratory that will contribute importantly to progress in the autism field. PUBLIC HEALTH RELEVANCE: Autism afflicts as many as 1 in 150 children in the United States and is a behavioral disorder with a high negative impact on individuals, their families, and our society. Understanding its biological basis in order to improve diagnosis and treatment are high priorities for public health. This project investigates a gene mutation discovered in a family with autism and how this leads biologically to the disease.

描述（由申请人提供）：我们已经鉴定了DACT 1基因座中的一种新的单核苷酸多态性（SNP），其改变了蛋白质保守结构域中进化上保守的氨基酸。我们假设，这种SNP在受影响的家庭中与自闭症的诊断相关联，改变了发育中神经元的蛋白质功能，从而导致疾病。我们已经开发了一个模型系统，在其中研究功能的相应蛋白质在出生后早期前脑神经元，一种细胞类型，可能是相关的自闭症发病机制。该系统使用了一种新的条件性基因敲除小鼠系在我的实验室产生的建立方法一起研究培养海马神经元（HCN）的成熟。我们的具体目标是回答以下问题：1. Dact1缺失对前脑神经元发育有影响吗？2.自闭症变体Dact 1蛋白与野生型Dact 1蛋白是否具有不同的生化特性？3.野生型和自闭症变异Dact1蛋白在神经发育过程中显示出功能差异吗？这是对国家精神卫生研究所的一笔探索性赠款，用于支持一名年轻研究人员的实验室，他是一名受过基础科学训练的精神病学家。我们的目标是迅速利用这个机会来研究野生型和自闭症相关变体Dact1蛋白在神经发育过程中的功能。希望这将导致在这个实验室的研究，这将有助于在自闭症领域的进展重要领域。公共卫生相关性：自闭症在美国每150名儿童中就有1名患有自闭症，这是一种行为障碍，对个人、家庭和社会都有很大的负面影响。了解其生物学基础以改善诊断和治疗是公共卫生的高度优先事项。该项目调查了在一个自闭症家庭中发现的基因突变，以及这种突变如何在生物学上导致这种疾病。

项目成果

Dact1 is a postsynaptic protein required for dendrite, spine, and excitatory synapse development in the mouse forebrain.

• DOI: 10.1523/jneurosci.0354-10.2010
• 发表时间: 2010-03-24
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Okerlund ND;Kivimäe S;Tong CK;Peng IF;Ullian EM;Cheyette BN
• 通讯作者: Cheyette BN