The role of focal adhesion kinase in CNS myelination

Virginia Commonwealth University, Richmond VA

Investigators

Abstract

DESCRIPTION (provided by applicant): The formation of the myelin sheath is a crucial step during development allowing for efficient conduction velocities to occur in the limited space of the mammalian central nervous system (CNS). During this event, oligodendrocytes (OLGs), the myelinating cells of the CMS, send out numerous processes that associate with axonal segments and ultimately enwrap them. For the maturation of OLG processes into myelin sheaths, interactions between the OLG plasma membrane and the extracellular matrix (ECM) are of vital importance. Therefore, the long term goal of this study is to investigate the role of OLG-ECM interactions during process outgrowth and myelination. The protein focal adhesion kinase (FAK) plays a central role in plasma membrane-ECM interactions. In addition, FAK protein and phosphorylation levels are altered during myelination. To further investigate the role of FAK for myelination we generated conditional FAK knockout mice, by using transgenic mice that express a tamoxifen-inducible Cre protein under the control of the proteolipid protein (PLP) promoter (PLP/CreERT) and mice that harbor homologous recombined FAK alleles in which the second kinase domain of FAK is flanked by loxP sites (FAKflox/flox). This system allows for an OLG-specific FAK knockout at a time point when OLGs are sending out processes before interacting with axons and beginning myelination. Based on our preliminary observations and the role of focal adhesion constituents for proper OLG process outgrowth, we hypothesize that FAK and in particular its phosphorylation state at the tyrosine 925 residue regulates OLG process outgrowth/remodeling and myelination. In particular our investigations proposed here will determine the role of FAK in 1) OLG myelination and myelin morphology in vivo and 2) OLG process outgrowth/remodeling in vitro. Improper myelination in pathological conditions, such as is seen in Multiple Sclerosis (MS) patients, results in persistent disabilities. Unfortunately repair of the myelin sheath under these conditions is limited and no curative treatment is currently available. Thus, a better understanding of the molecular mechanisms regulating OGL process outgrowth/remodeling and myelination will aid in identifying possible therapeutic targets to stimulate remyelination in such pathological conditions.