Project End Date April 2020
The goals are to use the zebrafish as a tool to study the function of genes associated with human mental health disorders, including schizophrenia, bipolar disorder and autism. We use the term animal “tool” in contrast with the more familiar notion of an animal “model”. While a model has the requirement of phenocopying a human disorder, a tool can provide insight into the disorder without phenocopying it. Our approach uses the attributes of the zebrafish, including ability to perform rapid loss and gain of function assays, and ability to perform chemical screens in whole embryos. The approach also rests on the hypotheses that 1) zebrafish homologs of human mental health disorder risk genes can be identified; 2) these genes function early during brain development and 3) human and zebrafish genes will show orthologous functions.
We have focused on function of the DISC1 gene (Disrupted In Schizophrenia), a schizoprenia risk gene. We have shown that DISC1 modulates Wnt signaling during zebrafish brain and somite development, and that the fish and human genes have interchangeable function. We are also analyzing zebrafish homologs of human genes corresponding to the human 16p11.2 region, associated with autism. In loss of function assays, 12/14 genes assayed show a brain phenotype, indicating that this region is rich in genes active during brain development. Future assays include use of chemical screening to identify modulators of selected mental health disorder risk gene activity.