Research Projects

This study aims to determine novel mitotic mechanisms that regulate neural specification, patterning, neurogenesis, and embryonic brain size. Mitotic aberrations result in abnormal tissue architecture, imbalance in the progenitor population, and premature/abnormal differentiation. Such anomalies in the neural tissue result in congenital defects such as megalencephaly (enlarged brain) and neurodevelopmental disorders like autism. We focus on studying mitosis-associated megalencephaly risk gene DIS3L2 in neurodevelopment to determine the molecular and cellular basis of megalencephaly. We will investigate the role of DIS3L2 by generating CRISPR-Cas9-based clinically relevant DIS3L2 mutants using zebrafish embryos. The mutants will be extensively characterized for neurodevelopmental defects, CNS development, and function. We will use transcriptomics and developmental biology approaches to identify changes in developmental processes and signaling pathways upon DIS3L2 depletion. Proteomic approaches such as immunoprecipitation and mass spectrometry will be used to identify interactors of DIS3L2 and delineate the molecular mechanism of DIS3L2-mediated developmental functions. Our preliminary data shows that DIS3L2 depletion results in defects in embryonic mitoses and neural fate specification. We propose to develop a DIS3L2-based megalencephaly zebrafish model to study pathophysiology and neurobehavioral anomalies. To our knowledge, there are no published reports that have answered these questions. This study will therefore identify key molecular mechanisms that govern early mitotic events in vertebrate neurodevelopment. The proposed experiments will improve our fundamental understanding about mitosis and neurogenesis, and could help us understand the mechanistic basis for over-growth syndromes, megalencephaly associated neurodevelopmental disorders like autism and cases of neuronal injury.