The efficient transmission of the neuronal action potential is essential for all aspects of nervous system function; and this process is intimately dependent on the insulation of the axon by the myelin membrane. The process of myelination is an exquisite and dynamic example of cell-cell interaction, which consists of the concentric wrapping of multiple layers of membrane around an axon. This process requires a series of highly orchestrated events that balance both extrinsic and intrinsic mechanisms to coordinate the spatiotemporal regulation of myelination. Demyelination as a result of disease or injury severely disrupts the efficient transmission of the action potential, ultimately resulting in a loss of function. In order to effectively treat these devastating conditions, it is essential to expand our knowledge concerning the generation and maturation of the myelin-forming cells and the processes that lead to myelination. A major goal of my research is to understand the fundamental molecular mechanisms involved in the development and differentiation of the myelin-forming cells of the central and peripheral nervous systems. More importantly, my research program attempts to identify novel target molecules and pathways in the development of potential therapeutics for demyelinating diseases and after nerve injury. Our recent findings and advances in in vitro and in vivo myelination techniques give us a rare opportunity to study and characterize these complex processes in a reduced system. Understanding the factors regulating these processes could prove invaluable for the treatment of demyelinating conditions such as Multiple Sclerosis and spinal cord injuries.
Oligodendrocytes are responsible for myelination of axons in the central nervous system (CNS). These terminally differentiated cells arise from oligodendrocyte precursor cells (OPCs), and migrate and proliferate along axons throughout the CNS. Upon reaching a final destination in either the brain or the spinal cord, an OPC must decide whether to differentiate into a mature myelinating cell or remain a precursor into adulthood. One major goal of my research is to understand the mechanisms involved in in this cell fate choice, as well as oligodendrocyte differentiation and myelination. Because adult OPCs exhibit a capacity for remyelination, understanding the factors regulating OPC cell fate decisions may be highly relevant to the treatment of demyelinating conditions. Our recent findings suggest that both OPC cell fate choices and the myelination process are heavily influenced by the microenvironment of a developing oligodendrocyte. A major focus of my research is to understand how the microenvironment coordinates the spatial and temporal regulation of differentiation and myelination. My laboratory will attempt to address three key questions.
- What mechanisms ensure the generation of the appropriate number of OPCs to coordinately match the local axonal environment?
- How does the microenvironment control differentiation, while maintaining a significant number of OPCs in an undifferentiated state?
- How does the developing nervous system generate the precise number of cells to differentiate and myelinate all of the axons perfectly?
We believe that a thorough understanding of the environmental impact on the differentiation and cell fate choices of OPCs has direct relevance to the application and efficacy of cell transplantation studies and remyelination paradigms. These projects also have widespread implications, highlighting general mechanisms of differentiation and cell fate that are influenced by both the environment and the intrinsic nature of progenitor cells. Current efforts to treat demyelinating conditions have fallen short not for lack of effort, but as a result of a tendency to focus primarily on the identification of specific signaling molecules that regulate differentiation and myelination. While the identification of these targets has been crucial in furthering our understanding of oligodendrocyte development, we believe that these studies alone are not sufficient to effectively treat demyelinating conditions. Instead, we must move beyond traditional approaches that currently define research efforts in the field. To this end, we propose that understanding the process of oligodendrocyte maturation requires an examination of how the biophysical interaction of OPCs with their environment can regulate differentiation. To understand the true relevance of intrinsic mechanisms involved in differentiation and cell fate, it is essential to define the manner in which these pathways are controlled by the surrounding environment. We believe that only through a synergistic understanding of the environmental regulation of intrinsic mechanisms will it be possible to define the appropriate conditions for the treatment of demyelinating diseases and other debilitating conditions.
Recent PublicationsRegulatory T cells promote myelin regeneration in the central nervous system.
Accelerated Remyelination during Inflammatory Demyelination Prevents Axonal Loss and Improves Functional Recovery.
Somatodendritic Expression of JAM2 Inhibits Oligodendrocyte Myelination.
Identification of the Kappa-Opioid Receptor as a Therapeutic Target for Oligodendrocyte Remyelination.
Activation of HIPK2 Promotes ER Stress-Mediated Neurodegeneration in Amyotrophic Lateral Sclerosis.
Dynamic Modulation of Myelination in Response to Visual Stimuli Alters Optic Nerve Conduction Velocity.
The environment rules: spatiotemporal regulation of oligodendrocyte differentiation.
Remodeling myelination: implications for mechanisms of neural plasticity.
Oligodendrocyte precursors migrate along vasculature in the developing nervous system.
Mechanostimulation Promotes Nuclear and Epigenetic Changes in Oligodendrocytes.
Astrocytes Underlie Neuroinflammatory Memory Impairment.
The myelin oligodendrocyte glycoprotein directly binds nerve growth factor to modulate central axon circuitry.
Phosphorylation of LKB1/Par-4 establishes Schwann cell polarity to initiate and control myelin extent.
Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis.
Astrocyte-encoded positional cues maintain sensorimotor circuit integrity.
Multiple sclerosis: Prospects and promise.
Stage-specific deletion of olig2 conveys opposing functions on differentiation and maturation of oligodendrocytes.
A rapid and reproducible assay for modeling myelination by oligodendrocytes using engineered nanofibers.