Johns Hopkins School of Medicine

My lab is focused on understanding fundamental mechanisms involved in brain development and brain function with an emphasis on how dysfunction in these mechanisms can result in neurodevelopmental and psychiatric disorders. By focusing on key developmental genes that are associated with psychiatric risk and related animal and stem cell models, my research group is both improving our primary understanding of brain development while also making significant inroads into identifying pathophysiological mechanisms underlying psychiatric disorders.

A major focus of my lab is to understand the function of Transcription Factor 4 (TCF4) gene. TCF4 is a clinically pleiotropic gene having association with schizophrenia and autism spectrum disorder (ASD). Autosomal dominant mutations in TCF4 result in Pitt Hopkins syndrome, a rare neurodevelopmental disorder with a variety of symptoms including developmental delays, intellectual disability, absent speech, and breathing abnormalities. My group has shown that TCF4 is an activity-dependent transcription factor that is a critical regulator of cortical development. We have shown that TCF4 regulates several developmental steps including cell fate specification, neuronal migration, cortical column formation, and neuronal excitability. More recently, we demonstrated that TCF4 directly regulates oligodendrocyte development and myelination. This work has led to the hypothesis that defects in myelination are a common pathophysiology across the autism spectrum. We are now working on genetic and pharmacological approaches to rescue myelination in PTHS models, with the goal of applying these therapeutic approaches more broadly to ASD.

Another primary focus of our lab is to identify etiological and pathophysiological mechanisms associated with schizophrenia. Due to the polygenic nature of schizophrenia, we are studying a large cohort of induced pluripotent stem cells (iPSCs) derived from patients diagnosed with schizophrenia and neurotypical individuals. We recently demonstrated that electrophysiological measures from cortical neurons derived from these patient iPSCs were corelated with the individual’s clinical and cognitive behaviors. These results suggest that iPSC-derived models may reflect aspects of the clinical features of schizophrenia opening the door to a new cellular model to study schizophrenia in the lab. In addition, several rare genetic variants of schizophrenia are now identified. We are using CRISPR/Cas9 to generate isogenic iPSC lines harboring these schizophrenia risk variants which is leading to a whole new set of iPSC-based models of schizophrenia.