A Drosophila Model for Williams Syndrome Cognitive Processing

威廉姆斯综合症认知处理的果蝇模型

• 批准号: 7876916
• 负责人: RALPH J GREENSPAN
• 金额: $ 24.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7876916
• 关键词: 7q11.23; Address; Adult; Affect; Anxiety; Appetitive Behavior; Attention; Behavior; Behavioral; Behavioral Assay; Behavioral Genetics; Biological Assay; Cardiovascular Diseases; Characteristics; Chromosome Band; Chromosome Deletion; Chromosomes, Human, Pair 7; Cognition; Cognitive; Complex; Disease; Drosophila genus; Drosophila melanogaster; Face; Foundations; Gene-Modified; Genes; Genetic; Genetic Models; Genetic Polymorphism; Genetic screening method; Genome; Head; Homologous Gene; Human; Human Genome; Image; Impairment; Individual; LIMK1 gene; Language Development; Live Birth; Modeling; Modification; Molecular Genetics; Mutation; Pathway Analysis; Persons; Phenotype; Population; Process; RNA; Role; Series; Space Perception; System; Testing; Visuospatial; Williams Syndrome; Work; behavior influence; fly; gene interaction; interest; mutant; null mutation; public health relevance; skills; social; tool; virtual reality; visual search; 7q11.23; Address; Adult; Affect; Anxiety; Appetitive Behavior; Attention; Behavior; Behavioral; Behavioral Assay; Behavioral Genetics; Biological Assay; Cardiovascular Diseases; Characteristics; Chromosome Band; Chromosome Deletion; Chromosomes, Human, Pair 7; Cognition; Cognitive; Complex; Disease; Drosophila genus; Drosophila melanogaster; Face; Foundations; Gene-Modified; Genes; Genetic; Genetic Models; Genetic Polymorphism; Genetic screening method; Genome; Head; Homologous Gene; Human; Human Genome; Image; Impairment; Individual; LIMK1 gene; Language Development; Live Birth; Modeling; Modification; Molecular Genetics; Mutation; Pathway Analysis; Persons; Phenotype; Population; Process; RNA; Role; Series; Space Perception; System; Testing; Visuospatial; Williams Syndrome; Work; behavior influence; fly; gene interaction; interest; mutant; null mutation; public health relevance; skills; social; tool; virtual reality; visual search

DESCRIPTION (provided by applicant): Williams syndrome (WS) is a neurodevelopmental condition that is caused by a hemizygous deletion of roughly 1.5-1.8 megabases, a region of chromosome band 7q11.23 that contains about 28 genes. Found in 1 in 7500-20,000 live births, persons with WS have characteristic facial features, congenital and adult cardiovascular disease, and distinctive cognitive and behavioral characteristics. The cognitive phenotypes associated with WS include a delay in early language acquisition, profound impairments in visual-spatial skills. WS individuals can be very social and friendly, or also suffer from nonsocial anxiety. This proposal outlines a plan to develop a behavioral/genetic model in Drosophila melanogaster to study the distinctive cognitive phenotype affecting visuospatial processing found in humans with hemizygous deletions in chromosome 7 known as Williams Syndrome (WS). Specifically, we propose to study the respective roles of LIMK1 and STX1A on this phenotype in our model, and to address the inconsistency of the human findings on the influence of hemizigosity for these genes, by testing the effects of specific alterations in genetic background in our model. We will then use the tools of Drosophila genetics to identify the key interacting genes. The fruit fly has emerged in recent years not only as a powerful experimental system for understanding how genes influence phenotypes, but also for the sophistication of its behavioral repertoire. Working with behavioral assays for spatial attention that we have previously employed in the fruit fly and which we will enhance, we will test the effect on visuospatial processing of hemizygosity for the homologs of each of these genes in Drosophila, and then perform a series of genetic and molecular analyses to identify interacting genes that modify the phenotype. The genes so identified may then serve as candidates for testing and understanding behavioral inconsistencies among WS individuals with otherwise similar deletions. Aim 1: Test fruit flies hemizygous for null mutations of LIMK1 or Syx1A in Drosophila for spatial attention. After being placed on a common genetic background, mutations in LIMK11 and Syx1A 229 will be tested in two paradigms for spatial attention: a sensitive individual fly assay in a virtual reality flight arena, and a more efficient population maze assay for spatial discrimination. Aim 2: Enhance the sophistication of the visuospatial assays for flies by introducing a spatial construction component. Test the ability of Drosophila to combine previously recognized images into more complex images in modifications of the flight arena and maze assays. Test LIMK11 and Syx1A 229 hemizygotes for this ability. Aim 3: Test influence of genes known already to interact with LIMK1 or Syx1A in Drosophila for modification of their effects on visuospatial processing. Construct fly strains doubly heterozygous for LIMK11 and ___, _____, and ____, or for Syx1A 229 and ___, _____, and ____, and test in original and modified paradigms. Aim 4: Perform microarray analyses to compare gene interactions between mutant combinations showing modification of the visuospatial phenotypes vs. those that do not. RNA from the heads of flies will be analyzed by whole genome microarrays from doubly heterozygous strains showing phenotypic interactions and compared with strains showing no interactions. Network analysis will be applied to identify key interactors. PUBLIC HEALTH RELEVANCE: The study of genes and cognition has become an exciting field. However, genes that significantly affect cognition and behavior have been notoriously hard to locate within the human genome. Williams syndrome (WS) is a chromosome deletion disorder with interesting behavioral and cognitive phenotypic components, and the loss of genes within the WS deletion is responsible for these phenotypic characteristics. Accordingly, the study of WS gives us the opportunity to identify, firsthand, genes that influence behavior and cognition.

描述（由申请人提供）：威廉姆斯综合征（WS）是一种神经发育状况，是由大约1.5-1.8兆巴的半基质缺失引起的，这是染色体带7Q11.23的区域，其中包含大约28个基因。 WS患者在7500-20,000个活产中发现了1500-20,000人，具有特征性的面部特征，先天性和成人心血管疾病以及独特的认知和行为特征。与WS相关的认知表型包括延迟早期语言获取，视觉空间技能的深远障碍。 WS个人可能非常社交和友好，或者也患有非社交焦虑。 该提议概述了一个计划在果蝇中开发行为/遗传模型的计划，以研究影响染色体上半正如Williams综合征（WS）中半合子缺失的人类中观察到视觉空间处理的独特认知表型。具体而言，我们建议在我们的模型中研究Limk1和STX1A在该表型上的各自作用，并通过测试我们模型中遗传背景中特定变化的影响，以解决人类发现对这些基因的半化作用的不一致性。然后，我们将使用果蝇遗传学的工具来识别关键相互作用基因。近年来，果蝇出现了，不仅是一种强大的实验系统，用于理解基因如何影响表型，而且是为了使其行为库的复杂性。 我们以前在果蝇中使用过的行为测定法，并将其增强，我们将测试对果蝇中每个基因的同源物的视觉空间处理的影响，然后进行一系列遗传和分子分析，以鉴定相互作用的基因，以修饰材料。然后，被鉴定出的基因可以作为测试和理解其他类似缺失的人的行为不一致的候选者。 AIM 1：测试果蝇中limk1或syx1a的无效突变的果蝇在果蝇中引起空间注意力。将其放置在常见的遗传背景之后，Limk11和Syx1a 229中的突变将在两个范式中进行空间关注：虚拟现实飞行领域中的敏感个体飞行测定，以及更有效的人群迷宫测定法以进行空间歧视。 AIM 2：通过引入空间构造组件来增强视觉空间测定的复杂性。测试果蝇在飞行竞技场和迷宫测定法的修改中将先前识别图像组合到更复杂图像中的能力。测试Limk11和Syx1a 229半合子为此能力。 目标3：果蝇中已知已经与limk1或syx1a相互作用的基因的测试影响，以改变其对视觉空间加工的影响。构造蝇flains的lighlains在limk11和___，_____和____或syx1a 229和___，_____和____和____和____和____和____，并以原始和修改的范例进行测试。 AIM 4：执行微阵列分析，以比较突变体组合之间的基因相互作用，显示了视觉空间表型与不进行的修饰。蝇头的RNA将通过双重杂合菌株的整个基因组微阵列分析，显示出表型相互作用，并与没有相互作用的菌株进行比较。网络分析将应用于识别关键交互者。 公共卫生相关性：基因和认知的研究已成为一个令人兴奋的领域。然而，众所周知，很难将显着影响认知和行为的基因定位在人类基因组中。威廉姆斯综合征（WS）是一种具有有趣的行为和认知表型成分的染色体缺失障碍，WS缺失内基因的丧失是这些表型特征的原因。因此，WS的研究使我们有机会识别影响行为和认知的基因。