Our lab focuses on understanding the cellular and transcriptional mechanisms regulating myelination and the extra cellular matrix during development and their role in disease and injury.Dhananjay "Dan" Yellajoshyula's Biography
Much of our understanding of neural circuits and nervous system function has focused on the connectivity of individual neurons. However, fundamental features of nervous system development, function and plasticity are regulated by interactions outside of individual neurons by the extracellular matrix (ECM) and various glial cells. One example is myelination, the wrapping of axons by layers of lipid membrane by oligodendrocytes (OLs), 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. ECM composition strongly influences the development of the oligodendrocyte lineage, which in turn plays an essential role in circuit plasticity and key aspects of development. Our central goal is to understand the interplay of glial cells and ECM and their contributions to brain development and disease.
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.
Full Publications Can Be Found Here
Yellajoshyula D, Liang CC, Pappas SS, Penati S, Yang A, Mecano R, Kumaran R, Jou S, Cookson MR, Dauer WT (2017) The DYT6 Dystonia Protein THAP1 Regulates Myelination within the Oligodendrocyte Lineage. Dev Cell 42(1): 52-67.e4, 2017. PM28697333.
Yellajoshyula D, Pappas SS, Rogers AE, Choudhury B, Reed X, Ding J, et al. THAP1 modulates oligodendrocyte maturation by regulating ECM degradation in lysosomes. Proc Natl Acad Sci U S A. 2021 Aug 3;118(31):e2100862118. PMID: 34312226; PMCID: PMC8346877.
Yellajoshyula, D*, Abigail Rogers, Audrey J. Kim, Sumin Kim, Samuel S. Pappas and Dauer, William T*: A pathogenic THAP1 DYT6 dystonia mutation causes hypomyelination and loss of YY1 binding. Hum Mol Genet. 2021 Oct 23. doi: 10.1093/hmg/ddab310. Epub ahead of print. PMID: 34686877.
Yellajoshyula D*, Pappas SS, Dauer WT. Oligodendrocyte and Extracellular Matrix Contributions to Central Nervous System Motor Function: Implications for Dystonia. Mov Disord. 2022 Jan 6. doi: 10.1002/mds.28892. Epub ahead of print. PMID: 34989453.