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Integrins direct Src family kinases to regulate distinct phases of oligodendrocyte development.

Colognato H, Ramachandrappa S, Olsen IM, ffrench-Constant C - J. Cell Biol. (2004)

Bottom Line: Specific integrins expressed on oligodendrocytes, the myelin-forming cells of the central nervous system, promote either differentiation and survival or proliferation by amplification of growth factor signaling.Fyn associates with alpha6beta1 and is required to amplify platelet-derived growth factor survival signaling, to promote myelin membrane formation, and to switch neuregulin signaling from a phosphatidylinositol 3-kinase to a mitogen-activated protein kinase pathway (thereby changing the response from proliferation to differentiation).However, earlier in the lineage Lyn, not Fyn, is required to drive alphaVbeta3-dependent progenitor proliferation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Cambridge, Cambridge CB21QP, England, UK. colognato@pharm.sunysb.edu

ABSTRACT
Specific integrins expressed on oligodendrocytes, the myelin-forming cells of the central nervous system, promote either differentiation and survival or proliferation by amplification of growth factor signaling. Here, we report that the Src family kinases (SFKs) Fyn and Lyn regulate each of these distinct integrin-driven behaviors. Fyn associates with alpha6beta1 and is required to amplify platelet-derived growth factor survival signaling, to promote myelin membrane formation, and to switch neuregulin signaling from a phosphatidylinositol 3-kinase to a mitogen-activated protein kinase pathway (thereby changing the response from proliferation to differentiation). However, earlier in the lineage Lyn, not Fyn, is required to drive alphaVbeta3-dependent progenitor proliferation. The two SFKs respond to integrin ligation by different mechanisms: Lyn, by increased autophosphorylation of a catalytic tyrosine; and Fyn, by reduced Csk phosphorylation of the inhibitory COOH-terminal tyrosine. These findings illustrate how different SFKs can act as effectors for specific cell responses during development within a single cell lineage, and, furthermore, provide a molecular mechanism to explain similar region-specific hypomyelination in laminin- and Fyn-deficient mice.

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Newly formed oligodendrocytes require Fyn for laminin-mediated amplification of survival. SFK-depleted progenitors were differentiated on PDL or laminin-2 (Lm2) for 4 d with increasing amounts of the soluble growth factors PDGF or neuregulin (NRG). Survival was evaluated using TUNEL on a YFP/GalC double-positive cell population (transfected, newly formed oligodendrocytes). Low, medium, and high amounts of growth factors are depicted by light gray, dark gray, and black bars, respectively. Error bars represent SD. (A) Fyn depletion caused a significant shift in the PDGF dose–response curve when cells were differentiated on Lm2 (low, *, P < 0.05; medium, **, P < 0.01). (B) NRG-mediated survival was significantly reduced in Fyn-depleted cells differentiated on Lm2 (**, P < 0.01 for low, medium, and high concentrations of NRG), whereas no significant reduction in survival occurred in Lyn-depleted cells.
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fig4: Newly formed oligodendrocytes require Fyn for laminin-mediated amplification of survival. SFK-depleted progenitors were differentiated on PDL or laminin-2 (Lm2) for 4 d with increasing amounts of the soluble growth factors PDGF or neuregulin (NRG). Survival was evaluated using TUNEL on a YFP/GalC double-positive cell population (transfected, newly formed oligodendrocytes). Low, medium, and high amounts of growth factors are depicted by light gray, dark gray, and black bars, respectively. Error bars represent SD. (A) Fyn depletion caused a significant shift in the PDGF dose–response curve when cells were differentiated on Lm2 (low, *, P < 0.05; medium, **, P < 0.01). (B) NRG-mediated survival was significantly reduced in Fyn-depleted cells differentiated on Lm2 (**, P < 0.01 for low, medium, and high concentrations of NRG), whereas no significant reduction in survival occurred in Lyn-depleted cells.

Mentions: As oligodendrocyte progenitors exit the cell cycle and differentiate, they have an increased dependency on survival factors such as PDGF and neuregulin (NRG) (Barres et al., 1993; Canoll et al., 1996; Calver et al., 1998; Fernandez et al., 2000). Laminins that are found in myelinating axon tracts can potentiate the effects of these soluble survival factors (Frost et al., 1999; Colognato et al., 2002). We evaluated the ability of newly formed oligodendrocytes (defined by expression of the lineage marker galactocerebroside [GalC]) to respond to survival factors in the presence of Lm2 after depletion of individual SFKs. Cells were differentiated for 4 d with increasing doses of PDGF or NRG, and were evaluated for survival by TUNEL assays on double-labeled GFP/GalC-positive cells (Fig. 4).


Integrins direct Src family kinases to regulate distinct phases of oligodendrocyte development.

Colognato H, Ramachandrappa S, Olsen IM, ffrench-Constant C - J. Cell Biol. (2004)

Newly formed oligodendrocytes require Fyn for laminin-mediated amplification of survival. SFK-depleted progenitors were differentiated on PDL or laminin-2 (Lm2) for 4 d with increasing amounts of the soluble growth factors PDGF or neuregulin (NRG). Survival was evaluated using TUNEL on a YFP/GalC double-positive cell population (transfected, newly formed oligodendrocytes). Low, medium, and high amounts of growth factors are depicted by light gray, dark gray, and black bars, respectively. Error bars represent SD. (A) Fyn depletion caused a significant shift in the PDGF dose–response curve when cells were differentiated on Lm2 (low, *, P < 0.05; medium, **, P < 0.01). (B) NRG-mediated survival was significantly reduced in Fyn-depleted cells differentiated on Lm2 (**, P < 0.01 for low, medium, and high concentrations of NRG), whereas no significant reduction in survival occurred in Lyn-depleted cells.
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Related In: Results  -  Collection

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fig4: Newly formed oligodendrocytes require Fyn for laminin-mediated amplification of survival. SFK-depleted progenitors were differentiated on PDL or laminin-2 (Lm2) for 4 d with increasing amounts of the soluble growth factors PDGF or neuregulin (NRG). Survival was evaluated using TUNEL on a YFP/GalC double-positive cell population (transfected, newly formed oligodendrocytes). Low, medium, and high amounts of growth factors are depicted by light gray, dark gray, and black bars, respectively. Error bars represent SD. (A) Fyn depletion caused a significant shift in the PDGF dose–response curve when cells were differentiated on Lm2 (low, *, P < 0.05; medium, **, P < 0.01). (B) NRG-mediated survival was significantly reduced in Fyn-depleted cells differentiated on Lm2 (**, P < 0.01 for low, medium, and high concentrations of NRG), whereas no significant reduction in survival occurred in Lyn-depleted cells.
Mentions: As oligodendrocyte progenitors exit the cell cycle and differentiate, they have an increased dependency on survival factors such as PDGF and neuregulin (NRG) (Barres et al., 1993; Canoll et al., 1996; Calver et al., 1998; Fernandez et al., 2000). Laminins that are found in myelinating axon tracts can potentiate the effects of these soluble survival factors (Frost et al., 1999; Colognato et al., 2002). We evaluated the ability of newly formed oligodendrocytes (defined by expression of the lineage marker galactocerebroside [GalC]) to respond to survival factors in the presence of Lm2 after depletion of individual SFKs. Cells were differentiated for 4 d with increasing doses of PDGF or NRG, and were evaluated for survival by TUNEL assays on double-labeled GFP/GalC-positive cells (Fig. 4).

Bottom Line: Specific integrins expressed on oligodendrocytes, the myelin-forming cells of the central nervous system, promote either differentiation and survival or proliferation by amplification of growth factor signaling.Fyn associates with alpha6beta1 and is required to amplify platelet-derived growth factor survival signaling, to promote myelin membrane formation, and to switch neuregulin signaling from a phosphatidylinositol 3-kinase to a mitogen-activated protein kinase pathway (thereby changing the response from proliferation to differentiation).However, earlier in the lineage Lyn, not Fyn, is required to drive alphaVbeta3-dependent progenitor proliferation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Cambridge, Cambridge CB21QP, England, UK. colognato@pharm.sunysb.edu

ABSTRACT
Specific integrins expressed on oligodendrocytes, the myelin-forming cells of the central nervous system, promote either differentiation and survival or proliferation by amplification of growth factor signaling. Here, we report that the Src family kinases (SFKs) Fyn and Lyn regulate each of these distinct integrin-driven behaviors. Fyn associates with alpha6beta1 and is required to amplify platelet-derived growth factor survival signaling, to promote myelin membrane formation, and to switch neuregulin signaling from a phosphatidylinositol 3-kinase to a mitogen-activated protein kinase pathway (thereby changing the response from proliferation to differentiation). However, earlier in the lineage Lyn, not Fyn, is required to drive alphaVbeta3-dependent progenitor proliferation. The two SFKs respond to integrin ligation by different mechanisms: Lyn, by increased autophosphorylation of a catalytic tyrosine; and Fyn, by reduced Csk phosphorylation of the inhibitory COOH-terminal tyrosine. These findings illustrate how different SFKs can act as effectors for specific cell responses during development within a single cell lineage, and, furthermore, provide a molecular mechanism to explain similar region-specific hypomyelination in laminin- and Fyn-deficient mice.

Show MeSH
Related in: MedlinePlus