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Our lab work focuses on understanding the cellular and transcriptional mechanisms regulating the development of oligodendrocyte lineage and the extra cellular matrix during development. And how their dysregulation of these mechanisms contributes to neurodevelopmental disorders. To achieve this goal our lab uses mouse genetics and in vitro cultures. Our ongoing studies are focused on the mouse models on an inherited movement disorder DYT6 dystonia, that disrupts CNS motor function resulting from mutations to a transcription factor, THAP1. Dystonia is a neurological movement disorder characterized by debilitating involuntary movements resulting from abnormal motor control circuitry in the CNS.

Transcriptional control of oligodendrocyte maturation during development and in dystonia

Prior studies from our group and others have demonstrated CNS hypomyelination from the conditional loss of the transcription factors THAP1 and YY1 in the oligodendrocyte lineage. Multiple reports have identified that both THAP1 and YY1 loss-of-function mutations as a cause of human dystonia, a neurological movement disorder affecting CNS motor function. We are currently investigating the newly defined THAP1-YY1 transcriptional network in regulating oligodendrocyte progenitor maturation during development and its role in establishing CNS motor function. Our long term goal is to identify other members of this newly defined transcriptional network using genomic and proteomic studies and their contribution to the pathology of dystonia.

Cellular pathways driving ECM homeostasis during development and in injury

CNS axon-glia interactions are profoundly influenced by the ECM, a complex three-dimensional milieu composed of fibrous proteins (e.g., collagen, elastin), glycosaminoglycans (GAGs, a class of long unbranched mucopolysaccharides), and GAG-modified proteins (proteoglycan or “GAG-PG”) . GAGs including CS- GAGs (and CSPGs) have been established to have profound role in regulating OL differentiation and axon regeneration in the context of injury. However, the sources and cellular mechanisms regulating GAG content and composition in the CNS during development are poorly defined. We will deploy genetic reagents and biochemical tools to define the how distinct CNS cell types contribute to generating and interacting with the brain ECM during development and their dysregulation in neurodevelopmental disorders and from injury. For more information, please visit the Yellajoshyula lab.