Periodic Reporting for period 2 - SZFunc (Functional Analysis of Schizophrenia Risk Gene RBM12)
Reporting period: 2020-09-01 to 2021-08-31
Schizophrenia is a devastating disease with substantial costs for society. Although the disease has been described for thousands of years, its biological basis is unknown and there are no biomarkers. Current treatment, antipsychotic drugs, alleviates only a subset of the symptoms. Our project aimed to use the association of truncating variants of RBM12 with schizophrenia to better understand the molecular pathology of the disease, potentially leading to new therapies. We used two model systems to study RBM12: mutant zebrafish lines created using CRISPR/Cas9 and HEK293 cells overexpressing alternate variants of RBM12.The zebrafish studies allowed us to learn about the effect of Rbm12 mutation on the brain and behavior, whereas the cell model led to new insights into the function of RBM12 at the molecular level. Together, our results enhance today's understanding of the molecular pathology of schizophrenia.
In zebrafish, we used Crispr/Cas9 to create Rbm12 alleles coding for early truncation of the protein. We find that that fish harboring one or two copies of these alleles show altered brain structure and behavior. In HEK293 cells, we used the FlpIn system to create cell lines expressing inducible, gfp-tagged wild-type or mutant RBM12. We used these lines to identify direct targets of RBM12, using iCLIP, as well as direct and indirect targets using RNA-seq. We are currently working on a manuscript reporting these findings.
Our results provide insight into the molecular mechanism behind schizophrenia as well as the connections of the disease to other mental disorders. These findings require additional research before they will be clinically useful but the new details we have uncovered provide promising leads into the processes that have gone awry in schizophrenia. Altering these processes at the molecular level should lead to amelioration of disease.