A Drosophila Model for Williams Syndrome Cognitive Processing

威廉姆斯综合症认知处理的果蝇模型

基本信息

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
项目类别：
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

项目摘要

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）是一种神经发育病症，由大约 1.5-1.8 兆碱基的半合子缺失引起，该区域是染色体带 7q11.23 的一个区域，包含约 28 个基因。每 7500-20,000 名活产儿中就有 1 人患有 WS，他们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早期语言习得延迟、视觉空间技能严重受损。 WS 个体可能非常社交和友善，但也可能患有非社交焦虑症。该提案概述了在果蝇中开发行为/遗传模型的计划，以研究在 7 号染色体半合子缺失（称为威廉姆斯综合症 (WS)）的人类中发现的影响视觉空间处理的独特认知表型。具体来说，我们建议在我们的模型中研究 LIMK1 和 STX1A 对这种表型的各自作用，并通过测试我们的模型中遗传背景的特定改变的影响来解决人类研究结果对这些基因的半异基因影响的不一致问题。模型。然后，我们将使用果蝇遗传学工具来识别关键的相互作用基因。近年来，果蝇的出现不仅成为了解基因如何影响表型的强大实验系统，而且还因其行为库的复杂性而出现。通过我们之前在果蝇中使用的空间注意力行为测定，我们将对其进行增强，我们将测试果蝇中每个基因的同源性半合性对视觉空间处理的影响，然后进行一系列遗传分析和分子分析来识别改变表型的相互作用基因。然后，如此鉴定的基因可以作为候选基因，用于测试和理解具有其他类似缺失的 WS 个体之间的行为不一致。目标 1：测试果蝇中半合子果蝇的 LIMK1 或 Syx1A 无效突变，以实现空间注意力。在置于共同的遗传背景下后，LIMK11 和 Syx1A 229 的突变将在两种空间注意力范例中进行测试：虚拟现实飞行竞技场中的敏感个体苍蝇测定，以及用于空间辨别的更有效的群体迷宫测定。目标 2：通过引入空间构建组件来提高果蝇视觉空间分析的复杂性。测试果蝇在修改飞行场地和迷宫测定中将先前识别的图像组合成更复杂图像的能力。测试 LIMK11 和 Syx1A 229 半合子的这种能力。目标 3：测试已知与果蝇中 LIMK1 或 Syx1A 相互作用的基因的影响，以修改它们对视觉空间处理的影响。构建 LIMK11 和 ___、_____ 和 ____，或 Syx1A 229 和 ___、_____ 和 ____ 的双杂合蝇品系，并在原始和修改的范例中进行测试。目标 4：进行微阵列分析，比较显示视觉空间表型改变的突变体组合与没有改变的突变体组合之间的基因相互作用。来自果蝇头部的RNA将通过来自显示表型相互作用的双杂合菌株的全基因组微阵列进行分析，并与没有显示相互作用的菌株进行比较。将应用网络分析来识别关键交互者。公共卫生相关性：基因和认知研究已成为一个令人兴奋的领域。然而，众所周知，在人类基因组中很难定位显着影响认知和行为的基因。威廉姆斯综合征 (WS) 是一种染色体缺失疾病，具有有趣的行为和认知表型成分，WS 缺失中基因的丢失是造成这些表型特征的原因。因此，WS 的研究使我们有机会直接识别影响行为和认知的基因。