Epigenetic regulation of nervous system development in health and disease
The cerebral cortex is the seat of sensory perception, decision-making, language, learning and memory. How this complex structure is brought about during development is a fascinating question in neurobiology. Chromatin and epigenetic regulations play a critical role in cortical development. Studying the chromatin regulatory mechanisms is important to our understanding of the fundamental process of building the brain and it is mutations in the very same networks, which lead to a range of neurodevelopmental disorders. The broad research aim of my laboratory in the Brain Development and Disease Mechanisms (BDDM) theme at inStem, is to understand chromatin-level control of brain development in health and in disease.

Mouse models of cortical development
At the fundamental level, we would like to explore the crosstalk between different chromatin complexes and tease out the interactions at the molecular level to understand the fine-tuning of gene expression of downstream targets and ultimately bring in-depth molecular insight into the dynamicity of the developing brain. This depth and rigour of understanding is best achieved in a mouse model of cortical development. To address these questions, we combine mouse genetics with functional genomics and protein biochemistry to identify downstream target genes and their interacting partners. For functional and cellular analysis of the identified target genes we perform, in utero electroporation, organotypic slice cultures, dissociated neuron/glia culture and retrograde and anterograde labelling of axon tracts to examine circuitry and connectivity in mice brain.

Human derived neurons and cerebral organoids
We further extend our work from basic to translational in trying to understand the cellular and molecular mechanisms of neurodevelopmental disorders like schizophrenia (SZ) and bipolar disorder(BPD). Mental illnesses have neurodevelopmental origins and are poorly understood due to lack of appropriate mouse models to adequately recapitulate the human disease at multiple levels. We will utilize the iPSC lines generated from clinically dense families with SZ and BPD in the Accelerator program for Discovery in Brain disorders using Stem cells (ADBS). We generate 2D and 3D cerebral organoid cultures and combine CRISPR-Cas gene editing to model neuropsychiatric disorders in a dish.

Dr. Muralidharan is a Wellcome Trust DBT India Alliance, Intermediate Fellowship awardee.