Wrapping of the myelin sheath around axons by oligodendrocytes (OLs) is critical for the rapid conduction of electrical signals that are required for normal functioning of the CNS. Myelination is a multistep process involving the proliferation of OL progenitors (OPCs), timely differentiation into OLs, ensheathment of axons and finally rapid expansion of myelin sheath during the peak of myelination followed by gradual growth in adulthood. While many regulators of the early stages of OL development have been identified, there are significant gaps in our understanding of the specific intracellular signaling events that are integrated within the OLs that control later phases of myelinogenesis to increase its thickness in proportion to axon caliber. Understanding this mechanism is clinically relevant since it is unclear why the myelin that is formed during remyelination in Multiple Sclerosis fails to achieve normal thickness. This proposal primarily addresses the important question of how myelin assembly and maintenance are regulated in the CNS, hypothesizing that ERK1/2-MAPK (Extracelluar Signal Regulated Kinases-1/2), important mediators of multiple external signals, plays a central role in these processes. This is based on our recent findings that mice lacking OL-specific expression of ERK1/2 fail to up- regulate the transcription of major myelin genes and are unable to generate thick myelin sheaths. This is independent of OPC proliferation, differentiation and ensheathment of axons since these events remain unaffected in the Erk1/2 knockout mice. These results represent an important conceptual paradigm shift as they suggest that OL differentiation/initiation and subsequent increase in myelin thickness are distinctly regulated, in contrast to the PNS, where one signal controls both OL differentiation and myelination. To obtain further insights into the role of ERK1/2 in the complex in vivo environment, we seek to address the following specific questions using a series of transgenic mice models with genetic loss or gain of ERK1/2 function.
In Aim I, using mice where ablation of Erk1/2 in mature OLs will be induced at a later point in development and in adulthood, we will examine the role of ERK1/2 on the long- term progression of myelin growth and maintenance in adulthood.
In Aim II, using mice where ERK1/2 activity will be elevated in OPCs and OLs during development or in mature OLs during adulthood, we will elucidate the role of ERK1/2 in OL development and myelin assembly during active myelination and in adulthood. Overall, a combination of state-of-the-art genetic loss- and gain-of-function approaches as proposed here are expected to enhance our understanding of the functional significance of ERK1/2 signaling both during OL differentiation and active myelin biogenesis, as well as to sustain its gradual growth and maintenance in adulthood, and to apply this knowledge for an informed intervention in the treatment of demyelinating diseases such as MS.
Wrapping of the myelin sheath around axons by oligodendrocytes is critical for the rapid conduction of electrical signals, required for the norma functioning of the CNS, as evident by serious functional impairment in demyelinating diseases such as Multiple Sclerosis (MS). Limited endogenous remyelination that occurs in early MS lesions is inefficient and insufficient to maintain long-term myelin stability, underscoring the ned to identify signals that promote efficient myelin growth and maintenance. In this application we will investigate the role of ERK1/2, important mediators of a key-signaling pathway, as potential signals driving developmental myelin assembly, as well as sustained myelin growth and maintenance in adulthood, with a long-term goal to apply this knowledge for designing strategies to promote efficient remyelination.
