Promoter-Driven Sustained ERK1/2 Activation Increases B-Cell Activation and Suppresses Experimental Autoimmune Encephalomyelitis.

The ERK1/2 signaling pathway promotes myelin wrapping during development and remyelination, and sustained ERK1/2 activation in the oligodendrocyte (OL) lineage results in hypermyelination of the CNS. We therefore hypothesized that increased ERK1/2 signaling in the OL lineage would 1) protect against immune-mediated demyelination due to increased baseline myelin thickness and/or 2) promote enhanced remyelination and thus functional recovery after experimental autoimmune encephalomyelitis (EAE) induction. mice that express a constitutively active form of MEK1 (the upstream activator of ERK1/2) in the OL lineage, exhibited a significant decrease in EAE clinical severity compared to controls.

ERK1/2 Activation in Preexisting Oligodendrocytes of Adult Mice Drives New Myelin Synthesis and Enhanced CNS Function.

Unlabelled: Growing evidence shows that mechanisms controlling CNS plasticity extend beyond the synapse and that alterations in myelin can modify conduction velocity, leading to changes in neural circuitry. Although it is widely accepted that newly generated oligodendrocytes (OLs) produce myelin in the adult CNS, the contribution of preexisting OLs to functional myelin remodeling is not known. Here, we show that sustained activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in preexisting OLs of adult mice is sufficient to drive increased myelin thickness, faster conduction speeds, and enhanced hippocampal-dependent emotional learning.

Intracellular signaling pathway regulation of myelination and remyelination in the CNS.

The restoration of myelin sheaths on demyelinated axons remains a major obstacle in the treatment of multiple sclerosis (MS). Currently approved therapies work by modulating the immune system to reduce the number and rate of lesion formation but are only partially effective since they are not able to restore lost myelin. In the healthy CNS, myelin continues to be generated throughout life and spontaneous remyelination occurs readily in response to insults.

Translational control of myelin basic protein expression by ERK2 MAP kinase regulates timely remyelination in the adult brain.

Successful myelin repair in the adult CNS requires the robust and timely production of myelin proteins to generate new myelin sheaths. The underlying regulatory mechanisms and complex molecular basis of myelin regeneration, however, remain poorly understood. Here, we investigate the role of ERK MAP kinase signaling in this process.

Signaling through ERK1/2 controls myelin thickness during myelin repair in the adult central nervous system.

Oligodendrocytes, the myelin-forming cells of the CNS, exquisitely tailor the thickness of individual myelin sheaths to the diameter of their target axons to maximize the speed of action potential propagation, thus ensuring proper neuronal connectivity and function. Following demyelinating injuries to the adult CNS, newly formed oligodendrocytes frequently generate new myelin sheaths. Following episodes of demyelination such as those that occur in patients with multiple sclerosis, however, the matching of myelin thickness to axon diameter fails leaving remyelinated axons with thin myelin sheaths potentially compromising function and leaving axons vulnerable to damage.

ERK1/ERK2 MAPK signaling is required to increase myelin thickness independent of oligodendrocyte differentiation and initiation of myelination.

Wrapping of the myelin sheath around axons by oligodendrocytes is critical for the rapid conduction of electrical signals required for the normal functioning of the CNS. Myelination is a multistep process where oligodendrocytes progress through a well coordinated differentiation program regulated by multiple extracellular growth and differentiation signals. The intracellular transduction of the extracellular signals that regulate myelination is poorly understood.

The ERK2 mitogen-activated protein kinase regulates the timing of oligodendrocyte differentiation.

Oligodendrocyte development is tightly controlled by a variety of extracellular growth and differentiation factors. The mitogen-activated protein kinases (MAPKs), ERK1 and ERK2, are critical intracellular signaling molecules important for transducing these extracellular signals. The extracellular signal-regulated kinases (ERKs) are ubiquitously expressed, coordinately regulated, and highly similar, but Erk2 deletion in mice is embryonic lethal whereas Erk1 deletion is not.

Restoring the balance between disease and repair in multiple sclerosis: insights from mouse models.

Multiple sclerosis (MS) is considered an autoimmune-mediated demyelinating disease that targets the central nervous system (CNS). Despite considerable research efforts over multiple decades, our understanding of the basic biological processes that are targeted in the disease and the mechanisms of pathogenesis are poorly understood. Consequently, current therapies directed at controlling the progression of the disease are limited in their effectiveness.

Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities.

Rett syndrome (RTT) is characterized by specific motor, cognitive, and behavioral deficits. Because several of these abnormalities occur in other disease states associated with alterations in aminergic neurotransmitters, we investigated the contribution of such alterations to RTT pathogenesis. We found that both individuals with RTT and Mecp2-null mice have lower-than-normal levels of aminergic metabolites and content.