Oligodendrocytes (OLGs), the myelinating cells of the central nervous system (CNS), undergo extensive changes in morphology when they mature first from bipolar OLG progenitors into premyelinating OLGs extending a complex and expanded process network and then into mature OLGs generating the myelin sheath. The morphological changes associated with this lineage progression are to a large extent driven by changes in the organization of the actin cytoskeleton, which require a well-coordinated dynamic turnover of actin filaments and are thought to be regulated by extracellular signals, which may, at least in part, be axon-derived. Despite intensive research, however, the signaling pathways involved in regulating such extracellular signal-regulated changes in actin cytoskeleton-driven OLG morphology, i.e. OLG morphogenesis, and CNS myelination are currently only poorly characterized. Notably, both changes in the extracellular milieu and a misregulation of actin cytoskeletal mechanisms have been proposed to contribute to the limitations in OLG morphogenesis and remyelination as seen within the CNS of the major demyelinating disease in human, Multiple Sclerosis (MS). Thus and in an attempt to identify novel therapeutic targets for the treatment of MS, our long-term goal is to identify and characterize signaling axes that promote developmental OLG morphogenesis and CNS myelination via an extracellular signal to actin cytoskeleton pathway but are misregulated within MS lesions. In this regard, our preliminary data suggest that a signaling axis involving the activity of sodium- dependent glutamate transporters and subsequent changes in the actin-binding activity of calcium/calmodulin- dependent protein kinase II (CaMKII) is critical for efficient OLG morphogenesis and the generation of a myelin sheath of proper thickness (g-ratio). Notably, our preliminary data together with previously published findings point toward a misregulation of this signaling axis within MS lesions. Based on our preliminary data, we thus formulate the central hypothesis that efficient myelination, i.e. the establishment of myelin with a proper g-ratio, is regulated by a glutamate transporter-CaMKII-actin cytoskeleton axis that is operative within differentiating OLGs. To address the above stated central hypothesis we propose the completion of the following two specific aims: 1) to characterize in vivo the role of the apparentl functionally predominant sodium-dependent glutamate transporter in differentiating OLGs, GLT-1, in regulating developmental myelination and 2) to characterize in vitro the role of the glutamate transporter-CaMKII-actin cytoskeleton axis in regulating OLG morphogenesis. We anticipate that these experiments will build the basis for continuing studies in which to define strategies to specifically target CaMKII's unique actin binding properties and/or GLT-1 signaling as an attempt toward the development of novel remyelination promoting therapeutic strategies and toward improving the treatment of neurologic diseases associated with CNS demyelination.

Public Health Relevance

Currently no curative treatments are available for neurologic diseases that are associated with central nervous system (CNS) demyelination such as the major human demyelinating disease Multiple Sclerosis (MS). As an attempt to better understand the molecular mechanisms that may be targeted for promoting myelin repair under pathologic conditions, the present grant application seeks to better understand the role of a glutamate transporter (GLT-1)-CaMKII-actin cytoskeleton axis in the regulation of oligodendrocyte morphogenesis and CNS myelination. The experiments to be completed as part of this exploratory grant proposal are anticipated to build the basis for continuing studies in which to further assess the role of this signaling axis in CNS myelination as well as remyelination and to thereby contribute to a better understanding on how to stimulate CNS repair under pathologic demyelinating conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS090901-01A1
Application #
8913374
Study Section
Special Emphasis Panel (ZRG1-MDCN-T (06))
Program Officer
Morris, Jill A
Project Start
2015-02-01
Project End
2017-01-31
Budget Start
2015-02-01
Budget End
2016-01-31
Support Year
1
Fiscal Year
2015
Total Cost
$190,625
Indirect Cost
$65,625
Name
Virginia Commonwealth University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Wheeler, Natalie A; Fuss, Babette (2016) Extracellular cues influencing oligodendrocyte differentiation and (re)myelination. Exp Neurol 283:512-30