Myelin, produced by the concentric wrapping of oligodendrocyte processes, is critical for the effective and timely communication between neurons in distant regions of the brain and spinal cord. During development, oligodendrocytes tailor the thickness of individual myelin sheaths to the diameter of their target axons to ensure appropriate neuronal function. The importance of myelination becomes obvious in demyelinating diseases such as multiple sclerosis (MS) where the eventual failure of myelin repair results in axonal degeneration and subsequent physical impairments. Furthermore, following episodes of demyelination and remyelination that occur early in the disease course of MS, the matching of myelin thickness to axon diameter fails potentially compromising function and leaving axons vulnerable to damage. How oligodendrocytes generate the appropriate thickness of myelin for an axon of defined size is unknown. A comprehensive understanding of the molecules and signaling pathways important for the generation of central nervous system (CNS) myelin is needed in order to design effective therapeutics tailored to enhance myelin repair in MS patients. Recently, we discovered that ERK1/2, key mediators of an evolutionarily conserved signaling pathway, are both necessary and sufficient for the expansion of the myelin sheath during development and following demyelinating injury in the adult mouse CNS. Based on these findings we hypothesize that ERK1/2 are critical regulators of CNS function through their oligodendrocyte-specific role in controlling myelin sheath growth. The proposed studies will use a series of transgenic mouse models with genetic loss or gain of ERK1/2 function to define the functional consequences of ERK1/2-mediated changes in myelin thickness. The use of an inducible system, where ERK1/2 is activated at specific stages of the oligodendrocyte-lineage, will allow us to tease apart both where and when activated ERK1/2 is most beneficial during myelin repair in two different models of demyelinating injury. Finally, we will test the role of important ERK1/2 interacting proteins to elucidate the molecular mechanisms and downstream targets of activated ERK1/2 important for myelin sheath growth. Defining the function of ERK1/2 in myelin sheath expansion will provide new insights to aid in the identification of novel therapeutic targets to promote myelin repair in patients with demyelinating diseases.
Multiple sclerosis is a devastating demyelinating disease where myelin repair fails resulting in the degeneration of axons. A better understanding of the molecules and signaling pathways important for the growth of the myelin sheath is needed to develop efficient strategies for myelin repair. In this application we seek to understand the role of ERK1/2, key mediators of a conserved signaling pathway, in myelination by defining the functional consequences of ERK1/2-mediated changes in myelin thickness during development and following demyelinating injury and by elucidating the downstream targets of ERK1/2 critical for myelin sheath expansion.
| Gaesser, Jenna M; Fyffe-Maricich, Sharyl L (2016) Intracellular signaling pathway regulation of myelination and remyelination in the CNS. Exp Neurol 283:501-11 |
| Jeffries, Marisa A; Urbanek, Kelly; Torres, Lester et al. (2016) ERK1/2 Activation in Preexisting Oligodendrocytes of Adult Mice Drives New Myelin Synthesis and Enhanced CNS Function. J Neurosci 36:9186-200 |
| Michel, Kelly; Zhao, Tianna; Karl, Molly et al. (2015) Translational control of myelin basic protein expression by ERK2 MAP kinase regulates timely remyelination in the adult brain. J Neurosci 35:7850-65 |
