Impairments of neuronal circuit formation during cortical development have been proposed as a major cause of neurodevelopmental disorders such as autism, epilepsy and intellectual disability. Severe forms of autism are co-morbid with intellectual disability, difficult to treat epilepsy and non-verbal status, and affect about 30% of patients diagnosed with autism. There are to date no current effective bio-therapeutics to treat patients affected by severe autism. Using a combination of genome edited and patient derived induced pluripotent stem cells (iPSCs) as well as mouse models, we hope to gain a better understanding of the underlying mechanisms that could eventually lead to the development of much needed therapeutics for difficult to treat autism.
Chromatin regulatory mechanisms in neuronal development A major research direction in the lab is focusing on how regulating the chromatin environment can modulate the structural development of neuronal connectivity. Chromatin regulators and transcription factors are overrepresented among the genes that have high risk variants associated with autism. We are focusing on a family of histone lysine methyltransferases and their role in neuronal development and disease. One of these proteins is called ASH1L, which when mutated has been associated with autistic behaviors, intellectual disability, seizures as well as other neurological presentations like Tourette syndrome. Our work suggest that the counteracting activities of ASH1L and the Polycomb Repressive Complex 2 group (PRC2) control gene expression in the developing brain modulating neuronal arborization and maturation. We posit that in cells where ASH1L has lost its function, there is nothing preventing the repressive activity of PRC2 which can then repress important ASH1L-driven gene programs necessary for typical neurodevelopment. We are using a combination of molecular, cellular and physiological techniques to interrogate the function of ASH1L in early human neuronal development.
Gene-environment interaction in autism spectrum disorders Autism spectrum disorders (ASD) are highly heritable. However, a significant proportion of ASD cases are of complex genetic etiology, an indication that this complexity might reflect the impact of gene-environment interactions. Genetic findings suggest that there is an overrepresentation of chromatin regulatory genes associated with autism. This suggests that environmental risk factors for ASD might exert their effect by modulating epigenetic mechanisms that alter neuronal development. We are using known environmental risk factors of autism (i.e. Valproic acid) as a tool to uncover epigenetic mechanisms of disease in human neurons.
Endomembrane compartment in autism and intellectual disability The establishment of neuronal circuitry during development depends on the careful orchestration of several cellular processes, including proper neuronal arborization and formation of functional synapses in response to neuronal activity. One major focus of our research has been the study of proteins that regulate the endomembrane compartment in neuronal morphogenesis and synaptogenesis. For example, the endosomal machinery controls receptor trafficking, recycling, degradation, and modulates signaling pathways important for neuronal growth, arborization, and synaptogenesis. Using genome-editing approaches in human iPSCs, we are targeting endomembrane proteins that have been associated with autism and intellectual disability. With this approach we hope to further elucidate common mechanisms in disorders of neuronal connectivity.