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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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Progenitors require Lyn, but not Fyn or Src, for PDGF-mediated proliferation on the αVβ3 ligand. Oligodendrocyte progenitors exposed to 0, 0.1, 1, or 10 ng/ml PDGF for 24 h were evaluated for the percentage of cells that incorporated BrdU. Profiles of control (black squares), Fyn-depleted (gray diamonds), Lyn-depleted (gray triangles), and Src-depleted (gray circles) cells are shown. On poly-d-lysine (PDL), all progenitors showed a similar dose-dependent increase in BrdU incorporation. In contrast, Lyn-depleted progenitors grown on the αVβ3 ligand fibronectin (FN) showed reduced BrdU incorporation (*, P < 0.05). Error bars represent SD.
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fig2: Progenitors require Lyn, but not Fyn or Src, for PDGF-mediated proliferation on the αVβ3 ligand. Oligodendrocyte progenitors exposed to 0, 0.1, 1, or 10 ng/ml PDGF for 24 h were evaluated for the percentage of cells that incorporated BrdU. Profiles of control (black squares), Fyn-depleted (gray diamonds), Lyn-depleted (gray triangles), and Src-depleted (gray circles) cells are shown. On poly-d-lysine (PDL), all progenitors showed a similar dose-dependent increase in BrdU incorporation. In contrast, Lyn-depleted progenitors grown on the αVβ3 ligand fibronectin (FN) showed reduced BrdU incorporation (*, P < 0.05). Error bars represent SD.

Mentions: To determine whether SFKs play a role in the responses of oligodendrocyte progenitors, we evaluated two essential functions of progenitors, proliferation and migration, using cells in which individual SFKs were depleted. PDGF is a mitogen for oligodendrocyte progenitors, and the proliferative response seen at physiological PDGF concentrations (0.1–1.0 ng/ml) can be enhanced by αVβ3 integrin engagement (Baron et al., 2002). We evaluated proliferation of SFK-depleted progenitors in the presence of increasing amounts of PDGF and in the presence or absence of the αVβ3 ligand FN (Fig. 2). With increasing PDGF concentrations, proliferation increased equally well in control and Fyn-, Lyn-, and Src-depleted progenitors grown on non-integrin substrate poly-d-lysine (PDL; Fig. 2, left). However, proliferation of Lyn-depleted cells on the αVβ3 ligand FN was reduced in response to physiological levels of PDGF (Fig. 2, right; *, P < 0.05). In contrast, depletion of Fyn or Src did not reduce PDGF-mediated proliferation on either substrate. Proliferation of progenitors grown on the α6β1 ligand laminin-2 (Lm2) also increased with increasing PDGF; however, SFK depletion had no effect (not depicted).


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)

Progenitors require Lyn, but not Fyn or Src, for PDGF-mediated proliferation on the αVβ3 ligand. Oligodendrocyte progenitors exposed to 0, 0.1, 1, or 10 ng/ml PDGF for 24 h were evaluated for the percentage of cells that incorporated BrdU. Profiles of control (black squares), Fyn-depleted (gray diamonds), Lyn-depleted (gray triangles), and Src-depleted (gray circles) cells are shown. On poly-d-lysine (PDL), all progenitors showed a similar dose-dependent increase in BrdU incorporation. In contrast, Lyn-depleted progenitors grown on the αVβ3 ligand fibronectin (FN) showed reduced BrdU incorporation (*, P < 0.05). Error bars represent SD.
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fig2: Progenitors require Lyn, but not Fyn or Src, for PDGF-mediated proliferation on the αVβ3 ligand. Oligodendrocyte progenitors exposed to 0, 0.1, 1, or 10 ng/ml PDGF for 24 h were evaluated for the percentage of cells that incorporated BrdU. Profiles of control (black squares), Fyn-depleted (gray diamonds), Lyn-depleted (gray triangles), and Src-depleted (gray circles) cells are shown. On poly-d-lysine (PDL), all progenitors showed a similar dose-dependent increase in BrdU incorporation. In contrast, Lyn-depleted progenitors grown on the αVβ3 ligand fibronectin (FN) showed reduced BrdU incorporation (*, P < 0.05). Error bars represent SD.
Mentions: To determine whether SFKs play a role in the responses of oligodendrocyte progenitors, we evaluated two essential functions of progenitors, proliferation and migration, using cells in which individual SFKs were depleted. PDGF is a mitogen for oligodendrocyte progenitors, and the proliferative response seen at physiological PDGF concentrations (0.1–1.0 ng/ml) can be enhanced by αVβ3 integrin engagement (Baron et al., 2002). We evaluated proliferation of SFK-depleted progenitors in the presence of increasing amounts of PDGF and in the presence or absence of the αVβ3 ligand FN (Fig. 2). With increasing PDGF concentrations, proliferation increased equally well in control and Fyn-, Lyn-, and Src-depleted progenitors grown on non-integrin substrate poly-d-lysine (PDL; Fig. 2, left). However, proliferation of Lyn-depleted cells on the αVβ3 ligand FN was reduced in response to physiological levels of PDGF (Fig. 2, right; *, P < 0.05). In contrast, depletion of Fyn or Src did not reduce PDGF-mediated proliferation on either substrate. Proliferation of progenitors grown on the α6β1 ligand laminin-2 (Lm2) also increased with increasing PDGF; however, SFK depletion had no effect (not depicted).

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