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Integrin signaling in oligodendrocytes and its importance in CNS myelination.

O'Meara RW, Michalski JP, Kothary R - J Signal Transduct (2010)

Bottom Line: To tailor novel therapeutics to halt or reverse disease process, we require a better understanding of oligodendrocyte biology and of the molecular mechanisms that initiate myelination.Integrin-mediated signaling is crucial to the proliferation, survival, and maturation of oligodendrocytes through the activation of downstream signaling pathways involved in cytoskeletal remodeling.Here, we review the current understanding of this important signaling axis and its role in oligodendrocyte biology and ultimately in the myelination of axons within the CNS.

View Article: PubMed Central - PubMed

Affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON, Canada K1H 8L6.

ABSTRACT
Multiple sclerosis is characterized by repeated demyelinating attacks of the central nervous system (CNS) white matter tracts. To tailor novel therapeutics to halt or reverse disease process, we require a better understanding of oligodendrocyte biology and of the molecular mechanisms that initiate myelination. Cell extrinsic mechanisms regulate CNS myelination through the interaction of extracellular matrix proteins and their transmembrane receptors. The engagement of one such receptor family, the integrins, initiates intracellular signaling cascades that lead to changes in cell phenotype. Oligodendrocytes express a diverse array of integrins, and the expression of these receptors is developmentally regulated. Integrin-mediated signaling is crucial to the proliferation, survival, and maturation of oligodendrocytes through the activation of downstream signaling pathways involved in cytoskeletal remodeling. Here, we review the current understanding of this important signaling axis and its role in oligodendrocyte biology and ultimately in the myelination of axons within the CNS.

No MeSH data available.


Related in: MedlinePlus

Integrins interact with other receptor types to mediate oligodendrocyte survival and proliferation. (a) Cooperative signaling between ErbB and integrin receptors. Binding of NRG to oligodendrocyte ErbB receptors normally evokes a proliferative response dependant on PI3K signaling. Upon α6β1-integrin ligation with LN2, NRG binding no longer induces PI3K activation, but rather initiates the MAPK survival response via Fyn signaling. (b) Joint regulatory control of survival in response to cooperative contactin and integrin receptor signaling. LN2 ligation of α6β1-integrin causes the dephosphorylation of Fyn's negative regulatory site Tyr531. L1 binding to the contactin receptor induces the phosphorylation of Tyr420 (activation site) and Tyr531. Integration of extracellular cues via contactin/integrin crosstalk facilitates the dynamic control of Fyn to execute cellular functions affecting survival. (c) PDGFR-a and α6β1-integrin interact in oligodendrocyte lipid rafts.  PI3K and Akt are activated upon concurrent ligation of PDGFR-α and α6β1-integrin with PDGF and LN2, respectively, to promote proliferation/survival.
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fig2: Integrins interact with other receptor types to mediate oligodendrocyte survival and proliferation. (a) Cooperative signaling between ErbB and integrin receptors. Binding of NRG to oligodendrocyte ErbB receptors normally evokes a proliferative response dependant on PI3K signaling. Upon α6β1-integrin ligation with LN2, NRG binding no longer induces PI3K activation, but rather initiates the MAPK survival response via Fyn signaling. (b) Joint regulatory control of survival in response to cooperative contactin and integrin receptor signaling. LN2 ligation of α6β1-integrin causes the dephosphorylation of Fyn's negative regulatory site Tyr531. L1 binding to the contactin receptor induces the phosphorylation of Tyr420 (activation site) and Tyr531. Integration of extracellular cues via contactin/integrin crosstalk facilitates the dynamic control of Fyn to execute cellular functions affecting survival. (c) PDGFR-a and α6β1-integrin interact in oligodendrocyte lipid rafts. PI3K and Akt are activated upon concurrent ligation of PDGFR-α and α6β1-integrin with PDGF and LN2, respectively, to promote proliferation/survival.

Mentions: Oligodendrocyte integrin receptors also modulate signaling by GFs other than PDGF, such as neuregulin-1 (NRG) [10, 12, 28, 34]. NRG is a soluble GF with a role in oligodendrocyte proliferation and survival [28]. NRG is predominantly expressed on the neuronal surface and acts as a survival and proliferative cue for oligodendrocytes through ErbB receptors [34]. On non-laminin substrates, NRG application to oligodendrocytes induces their proliferation via the PI3K pathway (Figure 2(a)[i]) [10]. Under these conditions, oligodendrocytes are sensitive to wortmannin treatment and thus depend on the PI3K pathway for survival. Once oligodendrocytes are seeded on LN2 (α6β1-integrin ligand), they lose their sensitivity to wortmannin, indicating an altered function of NRG. On LN2 rather, NRG activates the MAPK survival pathway (Figure 2(a)[ii]), as evidenced by increased phosphorylation (and thus inactivation) of the apoptotic protein BAD. Also, knockdown of SFK member Fyn prevents LN2-induced switching of the PI3K/MAPK pathways in response to soluble NRG [12]. These studies suggest that α6β1-integrin ligation mediates a switch in the function of NRG; without LN2 binding, NRG promotes a proliferative signal via PI3K. Conversely, upon LN2 adhesion, NRG no longer promotes proliferation but rather promotes differentiation/survival via MAPK, and Fyn is required for this signaling transition. Since certain laminin subunits are expressed on axons of the CNS [35–37], integrin-mediated adhesion of oligodendrocytes to axonal laminins may amplify NRG signaling via Fyn to promote differentiation/survival over proliferation. This enhanced survival is specifically mediated by α6β1-integrin and is also observed during oligodendrocyte contact with astrocytic laminins [38].


Integrin signaling in oligodendrocytes and its importance in CNS myelination.

O'Meara RW, Michalski JP, Kothary R - J Signal Transduct (2010)

Integrins interact with other receptor types to mediate oligodendrocyte survival and proliferation. (a) Cooperative signaling between ErbB and integrin receptors. Binding of NRG to oligodendrocyte ErbB receptors normally evokes a proliferative response dependant on PI3K signaling. Upon α6β1-integrin ligation with LN2, NRG binding no longer induces PI3K activation, but rather initiates the MAPK survival response via Fyn signaling. (b) Joint regulatory control of survival in response to cooperative contactin and integrin receptor signaling. LN2 ligation of α6β1-integrin causes the dephosphorylation of Fyn's negative regulatory site Tyr531. L1 binding to the contactin receptor induces the phosphorylation of Tyr420 (activation site) and Tyr531. Integration of extracellular cues via contactin/integrin crosstalk facilitates the dynamic control of Fyn to execute cellular functions affecting survival. (c) PDGFR-a and α6β1-integrin interact in oligodendrocyte lipid rafts.  PI3K and Akt are activated upon concurrent ligation of PDGFR-α and α6β1-integrin with PDGF and LN2, respectively, to promote proliferation/survival.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
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fig2: Integrins interact with other receptor types to mediate oligodendrocyte survival and proliferation. (a) Cooperative signaling between ErbB and integrin receptors. Binding of NRG to oligodendrocyte ErbB receptors normally evokes a proliferative response dependant on PI3K signaling. Upon α6β1-integrin ligation with LN2, NRG binding no longer induces PI3K activation, but rather initiates the MAPK survival response via Fyn signaling. (b) Joint regulatory control of survival in response to cooperative contactin and integrin receptor signaling. LN2 ligation of α6β1-integrin causes the dephosphorylation of Fyn's negative regulatory site Tyr531. L1 binding to the contactin receptor induces the phosphorylation of Tyr420 (activation site) and Tyr531. Integration of extracellular cues via contactin/integrin crosstalk facilitates the dynamic control of Fyn to execute cellular functions affecting survival. (c) PDGFR-a and α6β1-integrin interact in oligodendrocyte lipid rafts. PI3K and Akt are activated upon concurrent ligation of PDGFR-α and α6β1-integrin with PDGF and LN2, respectively, to promote proliferation/survival.
Mentions: Oligodendrocyte integrin receptors also modulate signaling by GFs other than PDGF, such as neuregulin-1 (NRG) [10, 12, 28, 34]. NRG is a soluble GF with a role in oligodendrocyte proliferation and survival [28]. NRG is predominantly expressed on the neuronal surface and acts as a survival and proliferative cue for oligodendrocytes through ErbB receptors [34]. On non-laminin substrates, NRG application to oligodendrocytes induces their proliferation via the PI3K pathway (Figure 2(a)[i]) [10]. Under these conditions, oligodendrocytes are sensitive to wortmannin treatment and thus depend on the PI3K pathway for survival. Once oligodendrocytes are seeded on LN2 (α6β1-integrin ligand), they lose their sensitivity to wortmannin, indicating an altered function of NRG. On LN2 rather, NRG activates the MAPK survival pathway (Figure 2(a)[ii]), as evidenced by increased phosphorylation (and thus inactivation) of the apoptotic protein BAD. Also, knockdown of SFK member Fyn prevents LN2-induced switching of the PI3K/MAPK pathways in response to soluble NRG [12]. These studies suggest that α6β1-integrin ligation mediates a switch in the function of NRG; without LN2 binding, NRG promotes a proliferative signal via PI3K. Conversely, upon LN2 adhesion, NRG no longer promotes proliferation but rather promotes differentiation/survival via MAPK, and Fyn is required for this signaling transition. Since certain laminin subunits are expressed on axons of the CNS [35–37], integrin-mediated adhesion of oligodendrocytes to axonal laminins may amplify NRG signaling via Fyn to promote differentiation/survival over proliferation. This enhanced survival is specifically mediated by α6β1-integrin and is also observed during oligodendrocyte contact with astrocytic laminins [38].

Bottom Line: To tailor novel therapeutics to halt or reverse disease process, we require a better understanding of oligodendrocyte biology and of the molecular mechanisms that initiate myelination.Integrin-mediated signaling is crucial to the proliferation, survival, and maturation of oligodendrocytes through the activation of downstream signaling pathways involved in cytoskeletal remodeling.Here, we review the current understanding of this important signaling axis and its role in oligodendrocyte biology and ultimately in the myelination of axons within the CNS.

View Article: PubMed Central - PubMed

Affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON, Canada K1H 8L6.

ABSTRACT
Multiple sclerosis is characterized by repeated demyelinating attacks of the central nervous system (CNS) white matter tracts. To tailor novel therapeutics to halt or reverse disease process, we require a better understanding of oligodendrocyte biology and of the molecular mechanisms that initiate myelination. Cell extrinsic mechanisms regulate CNS myelination through the interaction of extracellular matrix proteins and their transmembrane receptors. The engagement of one such receptor family, the integrins, initiates intracellular signaling cascades that lead to changes in cell phenotype. Oligodendrocytes express a diverse array of integrins, and the expression of these receptors is developmentally regulated. Integrin-mediated signaling is crucial to the proliferation, survival, and maturation of oligodendrocytes through the activation of downstream signaling pathways involved in cytoskeletal remodeling. Here, we review the current understanding of this important signaling axis and its role in oligodendrocyte biology and ultimately in the myelination of axons within the CNS.

No MeSH data available.


Related in: MedlinePlus