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Using zebrafish and chemical screening to define function of autism genes  

Roughly one percent of cases of autism are associated with deletions within a single region of chromosome 16, which contains nearly 30 genes. It is unclear which, and how many, of these genes are crucial in this association. Hazel Sive at the Whitehead Institute of Biomedical Research and her colleagues plan to determine which of these genes regulate brain development in zebrafish, in order to identify the genes that may contribute to the development of autism spectrum disorders. Zebrafish have become a powerful system in which to study questions that relate to human disease. The fish are a tool to study autism and not a traditional model, as the repertoire of fish behaviors is limited and cannot recapitulate the aspects of human behaviors impaired in autism. However, they are extremely valuable for many reasons: fish embryos develop rapidly, allowing rapid assays; they develop outside the mother, making observation of early stages simple; they are transparent, allowing analysis of brain development at a single-cell resolution in the living embryo; and both genetic and molecular screens can be readily performed to identify important genes. Of the 30 genes in the autism-associated region of chromosome 16 in humans, at least 25 have clear homologs in zebrafish. Many of these genes are expressed in the brain, including those that may regulate signaling pathways within cells, brain activity and gene expression. But how these genes function during normal brain development and by what mechanism they contribute to the etiology of autism remains unknown. In collaboration with Mark Daly of the Broad Institute at Massachusetts General Hospital, Sive plans to reduce the function of these genes using antisense oligonucleotides, which inhibit maturation of the messenger RNA corresponding to each gene. The researchers then plan to identify genes required for the formation of normal brain structure or neurons, and assess interactions between these genes by inhibiting the function of two or more genes at a time. Sive then plans to work with collaborator Steven Haggarty of the Broad Institute to look for small molecules that can reverse brain phenotypes. This strategy is uniquely feasible in zebrafish because large numbers of larvae can be used. These assays may, in the long term, shed light on which genes contribute to the etiology of autism, and offer insights that lead to autism treatment. Project Status


Funder Simons Foundation
Fiscal Year Funding $399,999.00
Current Award Period 2008-2011
Project Number 95091
Principal Investigator Sive, Hazel
Received ARRA Funding? No
Strategic Plan Question Question 4: Which Treatments And Interventions Will Help? (Treatments)
Subcategory Model Systems/Therapeutic Targets
Strategic Plan Objective Green dot: Objective has greater than or equal to the recommended funding. 4SB. Standardize and validate at least 20 model systems (e.g., cellular and/or animal) that replicate features of ASD and will allow identification of specific molecular targets or neural circuits amenable to existing or new interventions by 2012. IACC Recommended Budget: $75,000,000 over 5 years.
Federal or Private? Private
Institution Whitehead Institute for Biomedical Research
State/Country Massachusetts
Web Link 1 Using zebrafish and chemical screening to define function of autism genes (External web link)
Web Link 2 No URL available.
Web Link 3 No URL available.
New! History/Related Projects Using zebrafish and chemical screening to define function of autism genes | $395,496.50 | 2009 | 95091
Using zebrafish and chemical screening to define function of autism genes | $390,993.00 | 2008 | Project number unavailable