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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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Differentiation in response to laminin requires Fyn. (A) Decreased MBP expression in cells grown on laminin in the absence of Fyn. The percentage of SFK-depleted cells expressing the late stage differentiation marker MBP was expressed relative to the percentage of MBP+ in control cells. SFK-depleted cells grown on PDL (black bars) and on Lm2 (gray bars) were compared at days 2 and 4 after growth factor withdrawal. Error bars represent SD. (B) Myelin membrane classification scheme. Examples of MBP-expressing cells are shown. Stages 1, 2, and 3 show increasing levels of process outgrowth and branching, without myelin membrane, whereas stages 4, 5, and 6 show increasing levels of complexity and myelin membrane. (C) Fyn-depleted cells have less myelin membrane acquisition and complexity on Lm2 substrates. The percentage of cells within each category is shown for SFK-depleted YFP/MBP double-positive cells. Oligodendrocytes differentiated on PDL or Lm2 (control), black squares; Fyn(−), light gray squares; Lyn(−), gray triangles; and Src(−), dark gray circles (*, P < 0.050). Error bars represent SD. (D) Typical MBP-expressing (control) and Fyn-depleted oligodendrocytes grown on Lm2.
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fig6: Differentiation in response to laminin requires Fyn. (A) Decreased MBP expression in cells grown on laminin in the absence of Fyn. The percentage of SFK-depleted cells expressing the late stage differentiation marker MBP was expressed relative to the percentage of MBP+ in control cells. SFK-depleted cells grown on PDL (black bars) and on Lm2 (gray bars) were compared at days 2 and 4 after growth factor withdrawal. Error bars represent SD. (B) Myelin membrane classification scheme. Examples of MBP-expressing cells are shown. Stages 1, 2, and 3 show increasing levels of process outgrowth and branching, without myelin membrane, whereas stages 4, 5, and 6 show increasing levels of complexity and myelin membrane. (C) Fyn-depleted cells have less myelin membrane acquisition and complexity on Lm2 substrates. The percentage of cells within each category is shown for SFK-depleted YFP/MBP double-positive cells. Oligodendrocytes differentiated on PDL or Lm2 (control), black squares; Fyn(−), light gray squares; Lyn(−), gray triangles; and Src(−), dark gray circles (*, P < 0.050). Error bars represent SD. (D) Typical MBP-expressing (control) and Fyn-depleted oligodendrocytes grown on Lm2.

Mentions: The same factors that are critical for newly formed oligodendrocytes to survive also regulate entry into the myelin-forming stage of differentiation. To investigate whether SFKs regulate the ability of the ECM to alter oligodendrocyte differentiation, we evaluated MBP expression in the presence of integrin ligands in SFK-depleted cells. The percentage of MBP-expressing cells was determined, and the relative change between SFK-deficient cells and control cells is shown in Fig. 6 A. In cells differentiating on PDL, depletion of Fyn, Lyn, or Src had no effect on the percentage of cells that acquired MBP expression by days 2 or 4 (Fig. 6 A, black bars). In contrast, Fyn-depleted cells differentiated on Lm2 showed a large reduction in the percentage of cells expressing MBP, at both days 2 and 4 (Fig. 6 A, gray bars). However, Lyn- or Src-depleted cells showed no change in differentiation on either substrate.


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)

Differentiation in response to laminin requires Fyn. (A) Decreased MBP expression in cells grown on laminin in the absence of Fyn. The percentage of SFK-depleted cells expressing the late stage differentiation marker MBP was expressed relative to the percentage of MBP+ in control cells. SFK-depleted cells grown on PDL (black bars) and on Lm2 (gray bars) were compared at days 2 and 4 after growth factor withdrawal. Error bars represent SD. (B) Myelin membrane classification scheme. Examples of MBP-expressing cells are shown. Stages 1, 2, and 3 show increasing levels of process outgrowth and branching, without myelin membrane, whereas stages 4, 5, and 6 show increasing levels of complexity and myelin membrane. (C) Fyn-depleted cells have less myelin membrane acquisition and complexity on Lm2 substrates. The percentage of cells within each category is shown for SFK-depleted YFP/MBP double-positive cells. Oligodendrocytes differentiated on PDL or Lm2 (control), black squares; Fyn(−), light gray squares; Lyn(−), gray triangles; and Src(−), dark gray circles (*, P < 0.050). Error bars represent SD. (D) Typical MBP-expressing (control) and Fyn-depleted oligodendrocytes grown on Lm2.
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fig6: Differentiation in response to laminin requires Fyn. (A) Decreased MBP expression in cells grown on laminin in the absence of Fyn. The percentage of SFK-depleted cells expressing the late stage differentiation marker MBP was expressed relative to the percentage of MBP+ in control cells. SFK-depleted cells grown on PDL (black bars) and on Lm2 (gray bars) were compared at days 2 and 4 after growth factor withdrawal. Error bars represent SD. (B) Myelin membrane classification scheme. Examples of MBP-expressing cells are shown. Stages 1, 2, and 3 show increasing levels of process outgrowth and branching, without myelin membrane, whereas stages 4, 5, and 6 show increasing levels of complexity and myelin membrane. (C) Fyn-depleted cells have less myelin membrane acquisition and complexity on Lm2 substrates. The percentage of cells within each category is shown for SFK-depleted YFP/MBP double-positive cells. Oligodendrocytes differentiated on PDL or Lm2 (control), black squares; Fyn(−), light gray squares; Lyn(−), gray triangles; and Src(−), dark gray circles (*, P < 0.050). Error bars represent SD. (D) Typical MBP-expressing (control) and Fyn-depleted oligodendrocytes grown on Lm2.
Mentions: The same factors that are critical for newly formed oligodendrocytes to survive also regulate entry into the myelin-forming stage of differentiation. To investigate whether SFKs regulate the ability of the ECM to alter oligodendrocyte differentiation, we evaluated MBP expression in the presence of integrin ligands in SFK-depleted cells. The percentage of MBP-expressing cells was determined, and the relative change between SFK-deficient cells and control cells is shown in Fig. 6 A. In cells differentiating on PDL, depletion of Fyn, Lyn, or Src had no effect on the percentage of cells that acquired MBP expression by days 2 or 4 (Fig. 6 A, black bars). In contrast, Fyn-depleted cells differentiated on Lm2 showed a large reduction in the percentage of cells expressing MBP, at both days 2 and 4 (Fig. 6 A, gray bars). However, Lyn- or Src-depleted cells showed no change in differentiation on either substrate.

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