Fundamental features of nervous system development, function and plasticity are regulated by interactions outside of individual neurons and are supported by various glial cells and the extracellular matrix (ECM), which occupies ~20% of the adult brain. One example is myelination, the wrapping of axons with layers of lipid membrane by oligodendrocytes, which critically modifies their conductive properties. The majority of myelination of the central nervous system (CNS) occurs during childhood in humans and is associated with defining critical periods in the development of neural circuits. Myelination defects are well known in prevalent disorders such as multiple sclerosis and leukodystrophies, and more recently have been demonstrated to have a role in many neurodevelopment disorders including autism. ECM has a profound influence on myelination, synaptic plasticity and plays a critical role in the repair of injured axons and demyelinating disorders such as multiple sclerosis. Our recent studies have identified an important role for myelination and ECM in the neurological movement disorder, dystonia, which affects the motor function in the CNS.
Our lab is interested in studying the role of glial cells in brain ECM homeostasis and exploring the role of glia-ECM interactions in CNS myelination. We utilize cellular assays and animal models to study transcriptional and cellular mechanisms regulating myelination and ECM homeostasis in development and disease.
Current Projects
________________________________________________________________________________________
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 neurodevelopment disorders and from injury.
Yellajoshyula lab 