Principal Investigator Li-Huei Tsai
We previously demonstrated that the disrupted in schizophrenia 1 (DISC1) protein, the product of a gene whose translocation strongly increases the risk for mental illnesses in a large Scottish pedigree, regulates neural progenitor proliferation by directly binding to and inhibiting GSK3β to modulate canonical Wnt signaling. Current work in the lab is elucidating the biological functions for genes that have been identified as either schizophrenia or autism risk genes, or both, in the development of the brain. For example, we have validated several mRNA targets for the microRNA MIR137 gene, which has been associated with a risk for schizophrenia and for autism in genome-wide association studies. Using induced human neurons (iNs) from more than 20 individuals, we investigated a haplotype (rs1006737) located within an intron region of the voltage gated L-type calcium channel subunit gene CACNA1C, significantly associated with risk for bipolar disease, autism, and schizophrenia. Whole cell patch clamp recordings and quantitative PCR experiments demonstrated increased L-type channel current density as well as increased mRNA expression of CACNA1C in iNs homozygous for the risk genotype compared with non-risk genotypes. These studies indicate that the risk genotype at rs1006737 is associated with significant functional alterations in human iNs and suggest that current and future drugs that interact with calcium channel signaling hold promise for these disorders.
Currently, our neurodevelopmental research program is aimed towards investigating autism spectrum disorder (ASD) risk genes, especially those implicated in chromatin remodeling and epigenetic regulation of gene expression. CHD8 is a bromodomain containing chromatin remodeler. In addition to its role at the chromatin, CHD8 has been shown to interact with the Wnt pathway, which is also heavily implicated in ASD phenotypes. Multiple de novo CHD8 loss of function mutations (termination, frame shift) have been identified in ASD subjects. We would like to use CHD8 as a mean to understand the importance of chromatin remodeling and epigenetic gene regulation in brain development and how dysregulation of this process leads to severe mental illnesses such as ASD. As part of the Library of Integrated Network-based Cellular Signatures (LINCS) project headed by Jacob Jaffe at the Broad Institute, we are systemically perturbing dozens of ASD risk genes in human neural cells and conducting in-depth proteomic profiling to identify the cellular pathways that link these genes to autism-like phenotypes.