Myelin-mediated inhibition of oligodendrocyte precursor differentiation can be overcome by pharmacological modulation of Fyn-RhoA and protein kinase C signalling

Baer, Alexandra; Syed, Yasir Ahmed; Kang, Sung Ung; Mitteregger, Dieter; Vig, Raluca; ffrench‐Constant, Charles; Franklin, Robin J.M.; Altmann, Friedrich; Lubec, Gert; Kotter, Mark R.

doi:10.1093/brain/awn334

Cited by 186 publications

(181 citation statements)

References 90 publications

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“…Among several neurotrophic factors tested, the ciliary neurotrophic factor family was found to promote oligodendrocyte differentiation and remyelination [107]. More recently, pharmacologic induction of OPC differentiation by inhibition of RhoA-Rho-kinase II (ROCK-II), and/or protein kinase C signaling [108], or by anti-Leucine-rich repeats and Ig domain-containing, neurite outgrowth inhibitor (Nogo) receptor-interacting protein-1 (LINGO1) antibodies [109,110] accelerated remyelination. Statins and inhibitors of receptor tyrosine phosphatases are other pharmacologic agents that induce rodent [111] and human [112] oligodendrocyte differentiation.…”

Section: Myelin Regeneration Fails In Msmentioning

confidence: 99%

Cell Therapy for Multiple Sclerosis

Ben‐Hur

2011

Neurotherapeutics

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The spontaneous recovery observed in the early stages of multiple sclerosis (MS) is substituted with a later progressive course and failure of endogenous processes of repair and remyelination. Although this is the basic rationale for cell therapy, it is not clear yet to what degree the MS brain is amenable for repair and whether cell therapy has an advantage in comparison to other strategies to enhance endogenous remyelination. Central to the promise of stem cell therapy is the therapeutic plasticity, by which neural precursors can replace damaged oligodendrocytes and myelin, and also effectively attenuate the autoimmune process in a local, nonsystemic manner to protect brain cells from further injury, as well as facilitate the intrinsic capacity of the brain for recovery. These fundamental immunomodulatory and neurotrophic properties are shared by stem cells of different sources. By using different routes of delivery, cells may target both affected white matter tracts and the perivascular niche where the trafficking of immune cells occur. It is unclear yet whether the therapeutic properties of transplanted cells are maintained with the duration of time. The application of neural stem cell therapy (derived from fetal brain or from human embryonic stem cells) will be realized once their purification, mass generation, and safety are guaranteed. However, previous clinical experience with bone marrow stromal (mesenchymal) stem cells and the relative easy expansion of autologous cells have opened the way to their experimental application in MS. An initial clinical trial has established the probable safety of their intravenous and intrathecal delivery. Short-term follow-up observed immunomodulatory effects and clinical benefit justifying further clinical trials.

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Section: Myelin Regeneration Fails In Msmentioning

confidence: 99%

Cell Therapy for Multiple Sclerosis

Ben‐Hur

2011

Neurotherapeutics

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“…Third, injection of myelin debris into experimentally induced areas of demyelination in young animals results in impaired remyelination caused by the inhibition of precursor differentiation [43]. Recently, the Fyn-Rho-ROCK and protein kinase C (PKC) signaling pathways has been identified as critical mediators of myelin-associated inhibition [44].…”

Section: Myelin Debrismentioning

confidence: 99%

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

et al. 2011

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Regeneration of myelin sheaths (remyelination) after central nervous system demyelination is important to restore saltatory conduction and to prevent axonal loss. In multiple sclerosis, the insufficiency of remyelination leads to the irreversible degeneration of axons and correlated clinical decline. Therefore, a regenerative strategy to encourage remyelination may protect axons and improve symptoms in multiple sclerosis. We highlight recent studies on factors that influence endogenous remyelination and potential promising pharmacological targets that may be considered for enhancing central nervous system remyelination.

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“…Recently, co-stimulation of an integrin-contactin complex in OLs was found to amplify Fyn activation and promote myelination (16). Conversely, inhibition of OL differentiation by LINGO-1 or myelin protein extract mimicking the myelin debris generated by demyelination results in reduced Fyn activity (17,18). Fyn signals to several molecules that are important for OL morphological changes that require cytoskeletal rearrangement and process extension and elaboration, such as focal adhesion kinase (FAK), the Rho GTPases Rho, Rac1, and Cdc42, the Rho regulators p190 and p250 RhoGAP, Tau protein, and possibly via the kinase Cdk5 to paxillin (13, 19 -23).…”

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confidence: 99%

Protein-tyrosine Phosphatase α Acts as an Upstream Regulator of Fyn Signaling to Promote Oligodendrocyte Differentiation and Myelination

Wang

Xiao

et al. 2009

Journal of Biological Chemistry

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The tyrosine kinase Fyn plays a key role in oligodendrocyte differentiation and myelination in the central nervous system, but the molecules responsible for regulating Fyn activation in these processes remain poorly defined. Here we show that receptor-like protein-tyrosine phosphatase ␣ (PTP␣) is an important positive regulator of Fyn activation and signaling that is required for the differentiation of oligodendrocyte progenitor cells (OPCs). PTP␣ is expressed in OPCs and is up-regulated during differentiation. We used two model systems to investigate the role of PTP␣ in OPC differentiation: the rat CG4 cell line where PTP␣ expression was silenced by small interfering RNA, and oligosphere-derived primary OPCs isolated from wild-type and PTP␣-null mouse embryos. In both cell systems, the ablation of PTP␣ inhibited differentiation and morphological changes that accompany this process. Although Fyn was activated upon induction of differentiation, the level of activation was severely reduced in cells lacking PTP␣, as was the activation of Fyn effector molecules focal adhesion kinase, Rac1, and Cdc42, and inactivation of Rho. Interestingly, another downstream effector of Fyn, p190RhoGAP, which is responsible for Rho inactivation during differentiation, was not affected by PTP␣ ablation. In vivo studies revealed defective myelination in the PTP␣ ؊/؊ mouse brain. Together, our findings demonstrate that PTP␣ is a critical regulator of Fyn activation and of specific Fyn signaling events during differentiation, and is essential for promoting OPC differentiation and central nervous system myelination.Myelination is an essential feature of the vertebrate nervous system. The myelin sheath provides electrical insulation to axons and facilitates transmission of nerve impulses. Other important roles of myelin are to contribute to neuronal survival and development, as well as neurotransmission and synaptic activity (1). Deficiencies in myelination during development, or demyelination that can occur following injury or in diseases such as multiple sclerosis, lead to neurological disorders (2-4).The formation of the highly specialized multilamellar myelin sheath by oligodendrocytes (OLs) 3 in the CNS occurs early in development, following proliferation and migration of oligodendrocyte progenitor cells (OPCs) to their final axonal targets (5). The molecular mechanisms that regulate OPC differentiation and OL maturation and myelination remain poorly understood. Consistent with the physical juxtaposition of axons and enwrapping oligodendroglia, axonal signals have been identified that influence OPC differentiation and/or myelination, such the axonal ligands Jagged1 and contactin that engage the glial receptor Notch (6, 7). Other signals, such as those described below that are provided by components of the extracellular matrix or the presence or absence of growth factors, are also important in these processes.The Src family tyrosine kinase (SFK) Fyn is an essential participant and central coordinator of OL differentiation, maturatio...

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Myelin-mediated inhibition of oligodendrocyte precursor differentiation can be overcome by pharmacological modulation of Fyn-RhoA and protein kinase C signalling

Cited by 186 publications

References 90 publications

Cell Therapy for Multiple Sclerosis

Cell Therapy for Multiple Sclerosis

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

Protein-tyrosine Phosphatase α Acts as an Upstream Regulator of Fyn Signaling to Promote Oligodendrocyte Differentiation and Myelination

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