Using zebrafish and chemical screening to define function of autism genes
Hazel Sive, Ph.D.
Whitehead Institute for Biomedical Research
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.
Award #: 95091