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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 do not require Lyn for PDGF-mediated migration. Oligodendrocyte progenitors were concentrated in agarose drops and stimulated to migrate using PDGF. (A) Micrograph depicting Lyn-deficient cells (YFP+) migrating on FN in response to 1 ng/ml PDGF. (left) Anti-GFP; (right) phase. (B) Migration of SFK-deficient cells on FN in response to 1 ng/ml PDGF at day 2. Each bar depicts the mean migration distance of all YFP+ cells that have exited drops. Error bars represent SD.
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fig3: Progenitors do not require Lyn for PDGF-mediated migration. Oligodendrocyte progenitors were concentrated in agarose drops and stimulated to migrate using PDGF. (A) Micrograph depicting Lyn-deficient cells (YFP+) migrating on FN in response to 1 ng/ml PDGF. (left) Anti-GFP; (right) phase. (B) Migration of SFK-deficient cells on FN in response to 1 ng/ml PDGF at day 2. Each bar depicts the mean migration distance of all YFP+ cells that have exited drops. Error bars represent SD.

Mentions: Next, we tested whether progenitor migration in response to PDGF also involves a role for Lyn. The migration of SFK-depleted progenitor cells on ECM ligands was measured in the presence of varying amounts of PDGF. Progenitors were concentrated in a drop of low melting temperature agarose to establish a defined starting point, and the distance between the agarose boundary and each YFP+ cell was measured (Fig. 3). A drop that contains Lyn-depleted cells migrating on FN in the presence of 1 ng/ml PDGF is shown in Fig. 3 A. Unlike proliferation, no difference in PDGF-mediated migration was observed after the removal of Fyn, Lyn, or Src. The mean distances (micrometers) of migration on FN in response to 1 ng/ml PDGF were 71.2 ± 3.2 (control), 78.2 ± 13.2 (Fyn(−)), 72.6 ± 3.9 (Lyn(−)), and 73.0 ± 14.3 (Src(−)) (Fig. 3 B). Cells migrated further in response to 10 ng/ml PDGF; however, no significant difference among different SFK-depleted cells was observed: the mean migration distances (micrometers) were 117.9 ± 5.6 (control), 126.2 ± 16.8 (Fyn(−)), 130.3 ± 2.2 (Lyn(−)), and 120.2 ± 14.2 (Src(−)). Progenitors on PDL or Lm2 migrated less than cells on FN, but also exhibited no difference in their ability to migrate after SFK depletion (not depicted). Thus, oligodendrocyte progenitors have different requirements for Lyn during migration and proliferation in response to the same growth factor (PDGF) and ECM stimulus (FN).


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 do not require Lyn for PDGF-mediated migration. Oligodendrocyte progenitors were concentrated in agarose drops and stimulated to migrate using PDGF. (A) Micrograph depicting Lyn-deficient cells (YFP+) migrating on FN in response to 1 ng/ml PDGF. (left) Anti-GFP; (right) phase. (B) Migration of SFK-deficient cells on FN in response to 1 ng/ml PDGF at day 2. Each bar depicts the mean migration distance of all YFP+ cells that have exited drops. Error bars represent SD.
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Related In: Results  -  Collection

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fig3: Progenitors do not require Lyn for PDGF-mediated migration. Oligodendrocyte progenitors were concentrated in agarose drops and stimulated to migrate using PDGF. (A) Micrograph depicting Lyn-deficient cells (YFP+) migrating on FN in response to 1 ng/ml PDGF. (left) Anti-GFP; (right) phase. (B) Migration of SFK-deficient cells on FN in response to 1 ng/ml PDGF at day 2. Each bar depicts the mean migration distance of all YFP+ cells that have exited drops. Error bars represent SD.
Mentions: Next, we tested whether progenitor migration in response to PDGF also involves a role for Lyn. The migration of SFK-depleted progenitor cells on ECM ligands was measured in the presence of varying amounts of PDGF. Progenitors were concentrated in a drop of low melting temperature agarose to establish a defined starting point, and the distance between the agarose boundary and each YFP+ cell was measured (Fig. 3). A drop that contains Lyn-depleted cells migrating on FN in the presence of 1 ng/ml PDGF is shown in Fig. 3 A. Unlike proliferation, no difference in PDGF-mediated migration was observed after the removal of Fyn, Lyn, or Src. The mean distances (micrometers) of migration on FN in response to 1 ng/ml PDGF were 71.2 ± 3.2 (control), 78.2 ± 13.2 (Fyn(−)), 72.6 ± 3.9 (Lyn(−)), and 73.0 ± 14.3 (Src(−)) (Fig. 3 B). Cells migrated further in response to 10 ng/ml PDGF; however, no significant difference among different SFK-depleted cells was observed: the mean migration distances (micrometers) were 117.9 ± 5.6 (control), 126.2 ± 16.8 (Fyn(−)), 130.3 ± 2.2 (Lyn(−)), and 120.2 ± 14.2 (Src(−)). Progenitors on PDL or Lm2 migrated less than cells on FN, but also exhibited no difference in their ability to migrate after SFK depletion (not depicted). Thus, oligodendrocyte progenitors have different requirements for Lyn during migration and proliferation in response to the same growth factor (PDGF) and ECM stimulus (FN).

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