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
Source: PubMed


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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    • "Even though we show that a constitutive active b1-integrin cannot reverse the inhibitory effect of ephrin-A1 on process extension, we cannot exclude that the EphA receptors may directly inhibit signaling molecules downstream of the b1-integrins. Interesting candidate molecules include ILK, FAK, and Src-family kinases, which are all known to be regulated by EphA receptors in other cell types (Knoll and Drescher, 2004; Miao et al., 2000; Yamazaki et al., 2009), and also known to be important for process extension in the oligodendrocytes (Camara et al., 2009; Chun et al., 2003; Colognato et al., 2004; Forrest et al., 2009; Liang et al., 2004; O'Meara et al., 2013). Generally, the signaling pathways reported to be induced by forward and reverse signaling through the Eph-ephrin system are highly cell-type-specific. "
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    ABSTRACT: In the central nervous system, myelination of axons is required to ensure fast saltatory conduction and for survival of neurons. However, not all axons are myelinated, and the molecular mechanisms involved in guiding the oligodendrocyte processes toward the axons to be myelinated are not well understood. Only a few negative or positive guidance clues that are involved in regulating axo-glia interaction prior to myelination have been identified. One example is laminin, known to be required for early axo-glia interaction, which functions through α6β1 integrin. Here, we identify the Eph-ephrin family of guidance receptors as novel regulators of the initial axo-glia interaction, preceding myelination. We demonstrate that so-called forward and reverse signaling, mediated by members of both Eph and ephrin subfamilies, has distinct and opposing effects on processes extension and myelin sheet formation. EphA forward signaling inhibits oligodendrocyte process extension and myelin sheet formation, and blocking of bidirectional signaling through this receptor enhances myelination. Similarly, EphB forward signaling also reduces myelin membrane formation, but in contrast to EphA forward signaling, this occurs in an integrin-dependent manner, which can be reversed by overexpression of a constitutive active β1-integrin. Furthermore, ephrin-B reverse signaling induced by EphA4 or EphB1 enhances myelin sheet formation. Combined, this suggests that the Eph-ephrin receptors are important mediators of bidirectional signaling between axons and oligodendrocytes. It further implies that balancing Eph-ephrin forward and reverse signaling is important in the selection process of axons to be myelinated.
    ASN Neuro 09/2015; 7(5). DOI:10.1177/1759091415602859 · 4.02 Impact Factor
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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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