Focal Adhesion Kinase (FAK): a regulator of CNS myelination

Department of Anatomy and Neurobiology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
Journal of Neuroscience Research (Impact Factor: 2.59). 11/2009; 87(15):3456-64. DOI: 10.1002/jnr.22022
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The formation of the myelin sheath is a crucial step during development because it enables fast and efficient propagation of signals within the limited space of the mammalian central nervous system (CNS). During the process of myelination, oligodendrocytes actively interact with the extracellular matrix (ECM). These interactions are considered crucial for proper and timely completion of the myelin sheath. However, the exact regulatory circuits involved in the signaling events that occur between the ECM and oligodendrocytes are currently not fully understood. Therefore, in the present study we investigated the role of a known integrator of cell-ECM signaling, namely, focal adhesion kinase (FAK), in CNS myelination via the use of conditional (oligodendrocyte-specific) and inducible FAK-knockout mice (Fak(flox/flox): PLP/CreER(T) mice). When inducing FAK knockout just prior to and during active myelination of the optic nerve, we observed a significant reduction in the number of myelinated fibers on postnatal day 14. In addition, our data revealed a decreased number of primary processes extending from oligodendrocyte cell bodies at this postnatal age and on induction of FAK knockout. In contrast, myelination appeared normal on postnatal day 28. Thus, our data suggest that FAK controls the efficiency and timing of CNS myelination during its initial stages, at least in part, by regulating oligodendrocyte process outgrowth and/or remodeling.

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Available from: Jeffrey L Dupree, Oct 03, 2015
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    • "PlpCre/ESR1:NMIIB fl/fl (cKO) mice are viable, phenotypically normal, and born at the expected Mendelian ratios. PlpCre/ESR1 system has been extensively used to generate tamoxifen-induced, Cre-mediated recombination under the control of the myelin proteolipid protein (Plp1) promoter (Doerflinger et al., 2003; Forrest et al., 2009; Pillai et al., 2009); and previous studies have shown that upon treatment with tamoxifen, efficient recombination occurs in developing OPC and mature myelinating OL throughout the adult CNS as well as developing and mature Schwann cells in the peripheral nerve (Doerflinger et al., 2003; Leone et al., 2003). We performed our own assessment of PlpCre/ESR1 mediated-recombination 4 weeks after tamoxifen treatment of 8-week-old mice, using the reporter line Rosa26-mT/mG (Muzumdar et al., 2007) and confirmed extensive and efficient recombination in myelinating OL (MBP1, CC11) throughout corpus callosum, cortex, striatum, spinal cord, and optic nerve (Fig. 1) as well as NG2-(Fig. "
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    ABSTRACT: The oligodendrocyte (OL), the myelinating cell of the central nervous system, undergoes dramatic changes in the organization of its cytoskeleton as it differentiates from a precursor (oligodendrocyte precursor cells) to a myelin-forming cell. These changes include an increase in its branching cell processes, a phenomenon necessary for OL to myelinate multiple axon segments. We have previously shown that levels and activity of non-muscle myosin II (NMII), a regulator of cytoskeletal contractility, decrease as a function of differentiation and that inhibition of NMII increases branching and myelination of OL in coculture with neurons. We have also found that mixed glial cell cultures derived from NMIIB knockout mice display an increase in mature myelin basic protein-expressing OL compared with wild-type cultures. We have now extended our studies to investigate the role of NMIIB ablation on myelin repair following focal demyelination by lysolecithin. To this end, we generated an oligodendrocyte-specific inducible knockout model using a Plp-driven promoter in combination with a temporally activated CRE-ER fusion protein. Our data indicate that conditional ablation of NMII in adult mouse brain, expedites lesion resolution and remyelination by Plp+ oligodendrocyte-lineage cells when compared with that observed in control brains. Taken together, these data validate the function of NMII as that of a negative regulator of OL myelination in vivo and provide a novel target for promoting myelin repair in conditions such as multiple sclerosis. GLIA 2014.
    Glia 04/2014; 62(4). DOI:10.1002/glia.22627 · 6.03 Impact Factor
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    • "During differentiation of the oligodendrocyte progenitor cell line CG-4, FAK is phosphorylated and is required for process outgrowth through the activation of the Rho family GTPases, Cdc42 and Rac1 (Hoshina et al., 2007). Oligodendrocyte-specific ablation of FAK causes hypomyelination of small diameter axons in mice (Camara et al., 2009; Forrest et al., 2009). Reduced FAK activation and defects in myelination of small diameter axons are also seen following inhibition of signaling by integrin β1, a transmembrane protein that binds extracellular matrix proteins and recruits and activates various intracellular proteins, such as FAK (Camara et al., 2009). "
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    ABSTRACT: Myelination is essential for proper functioning of the CNS. In this study, we have identified a mouse mutation, designated furue, which causes tremors and hypomyelination in the CNS, particularly in the spinal cord, but not in the sciatic nerve of the PNS. In the spinal cord of the furue mice, myelination of small-diameter axons was dramatically reduced, and differentiation of oligodendrocytes, the myelin-forming cells in the CNS, was inhibited. We subsequently found that the furue mutation was associated with a transgene insertion into the teneurin-4 (Ten-4, Ten-m4/Odz4) gene, encoding a transmembrane protein of unknown function. Ten-4 was strongly expressed in the spinal cord of wild-type mice and was induced during normal oligodendrocyte differentiation. In contrast, in the furue mice, the expression of Ten-4 was absent. Differentiation and cellular process formation of oligodendrocytes were inhibited in primary cell culture from the furue mice. Cell differentiation and process formation were also inhibited in the oligodendrocyte progenitor cell line CG-4 after suppression of Ten-4 expression by shRNA. Furthermore, Ten-4 positively regulated focal adhesion kinase, an essential signaling molecule for oligodendrocyte process formation and myelination of small-diameter axons. These findings suggest that Ten-4 is a novel regulator of oligodendrocyte differentiation and that it plays a critical role in the myelination of small-diameter axons in the CNS.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 08/2012; 32(34):11586-99. DOI:10.1523/JNEUROSCI.2045-11.2012 · 6.34 Impact Factor
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    • "Thus Schwann cells with a conditional deletion of FAK fail to radially sort axons (Grove et al., 2007), similar to b1 integrin deficient Schwann cells (Feltri et al., 2002), yet also do not proliferate appropriately (unlike b1 integrin deficient Schwann cells), possibly reflecting FAK's ability to regulate RTK signaling (Feltri et al., 2002; Grove et al., 2007). Oligodendroglia with a conditional deletion of FAK both delay myelination as well as shift the axon size threshold for myelination, reminiscent of b1-integrin dominant negative phenotypes (Camara et al., 2009; Forrest et al., 2009; Lafrenaye and Fuss, 2010). Interestingly , FAK-deficient oligodendrocytes have different phenotypes in response to different ECM substrates: FAK-depleted oligodendrocytes do not exhibit the enhanced myelin membrane that is typically induced by laminin substrates, while FAK-depleted oligodendrocytes do not exhibit the retarded process growth that is typically induced by fibronectin substrates (Hoshina et al., 2007; Lafrenaye and Fuss, 2010). "
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    ABSTRACT: The health and function of the nervous system relies on glial cells that ensheath neuronal axons with a specialized plasma membrane termed myelin. The molecular mechanisms by which glial cells target and enwrap axons with myelin are only beginning to be elucidated, yet several studies have implicated extracellular matrix proteins and their receptors as being important extrinsic regulators. This review provides an overview of the extracellular matrix proteins and their receptors that regulate multiple steps in the cellular development of Schwann cells and oligodendrocytes, the myelinating glia of the PNS and CNS, respectively, as well as in the construction and maintenance of the myelin sheath itself. The first part describes the relevant cellular events that are influenced by particular extracellular matrix proteins and receptors, including laminins, collagens, integrins, and dystroglycan. The second part describes the signaling pathways and effector molecules that have been demonstrated to be downstream of Schwann cell and oligodendroglial extracellular matrix receptors, including FAK, small Rho GTPases, ILK, and the PI3K/Akt pathway, and the roles that have been ascribed to these signaling mediators. Throughout, we emphasize the concept of extracellular matrix proteins as environmental sensors that act to integrate, or match, cellular responses, in particular to those downstream of growth factors, to appropriate matrix attachment.
    Developmental Neurobiology 11/2011; 71(11):924-55. DOI:10.1002/dneu.20966 · 3.37 Impact Factor
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