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.
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.
