Skip navigation

Calls to Action

Dissecting the 16p11.2 CNV endophenotype in induced pluripotent stem cells

City: 
San Francisco
State/Province: 
CA
State/Province Full: 
California
Country: 
United States

Autism spectrum disorders (ASDs) are a heterogeneous group of disorders characterized by language impairment, deficits in social interactions and communication as well as stereotyped behaviors and restricted interests. Chromosomal abnormalities such as mutations and copy number variants (CNVs) - deletions or duplications of specific chromosomal regions, are associated with pathogenesis of ASDs. Specifically, a microdeletion or microduplication on chromosome 16 (16p11.2) confers susceptibility to ASDs. This region harbors ~25 genes, most of which are expressed in the human brain. Human neuroimaging studies have revealed abnormalities in the corpus callosum of 16p11.2 CNV carriers. Previous literature also suggests corpus callosum abnormalities in idiopathic ASDs. However, it is currently not known how the 16p11.2 CNV is associated with corpus callosum defects. Preliminary in silico analysis from our lab indicates that certain upstream regulators control several genes in the 16p11.2 region. One of these putative regulators is a key determinant during corpus callosum development and also has been previously associated with idiopathic ASDs. This project explores the hypothesis that manipulation of a ‘master regulator’ of specific 16p11.2 genes in induced pluripotent stem cells (iPSCs) derived from 16p11.2 CNV carriers will allow delineation of the gene expression patterns and of functional consequences by cellular assays. Using callosal bioassays such as axon outgrowth and guidance in neurons generated from 16p11.2-CNV carrier and non-carrier derived iPSCs, these studies will replicate the 16p11.2-associated cellular phenotypes and identify potential targets for therapeutic intervention. Finally, target-based strategies will be developed to rescue the phenotype in patient-derived neurons. This will encourage the development of novel strategies for prevention or treatment of ASDs. Once a gene target is identified, future projects will include small molecule screening.