Limits...
Glial growth factor/neuregulin inhibits Schwann cell myelination and induces demyelination.

Zanazzi G, Einheber S, Westreich R, Hannocks MJ, Bedell-Hogan D, Marchionni MA, Salzer JL - J. Cell Biol. (2001)

Bottom Line: Glial growth factor (GGF), a neuregulin-1 isoform, significantly inhibited myelination by preventing axonal segregation and ensheathment.Two other Schwann cell mitogens, fibroblast growth factor-2 and transforming growth factor-beta, inhibited myelination but did not cause demyelination, suggesting this effect is specific to the neuregulins.GGF treatment of myelinating cultures also induced phosphorylation of phosphatidylinositol 3-kinase, mitogen-activated protein kinase, and a 120-kD protein.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, New York University Medical Center, New York, New York 10016, USA.

ABSTRACT
During development, neuregulin-1 promotes Schwann cell proliferation and survival; its role in later events of Schwann cell differentiation, including myelination, is poorly understood. Accordingly, we have examined the effects of neuregulin-1 on myelination in neuron-Schwann cell cocultures. Glial growth factor (GGF), a neuregulin-1 isoform, significantly inhibited myelination by preventing axonal segregation and ensheathment. Basal lamina formation was not affected. Treatment of established myelinated cultures with GGF resulted in striking demyelination that frequently began at the paranodes and progressed to the internode. Demyelination was dose dependent and accompanied by dedifferentiation of Schwann cells to a promyelinating stage, as evidenced by reexpression of the transcription factor suppressed cAMP-inducible POU; a significant proportion of cells with extensive demyelination also proliferated. Two other Schwann cell mitogens, fibroblast growth factor-2 and transforming growth factor-beta, inhibited myelination but did not cause demyelination, suggesting this effect is specific to the neuregulins. The neuregulin receptor proteins, erbB2 and erbB3, are expressed on ensheathing and myelinating Schwann cells and rapidly phosphorylated with GGF treatment. GGF treatment of myelinating cultures also induced phosphorylation of phosphatidylinositol 3-kinase, mitogen-activated protein kinase, and a 120-kD protein. These results suggest that neuronal mitogens, including the neuregulins, may inhibit myelination during development and that activation of mitogen signaling pathways may contribute to the initial demyelination and subsequent Schwann cell proliferation observed in various pathologic conditions.

Show MeSH

Related in: MedlinePlus

GGF causes demyelination. Immunofluorescence micrographs of cocultures that had myelinated for 3 wk demonstrating normal myelination in control cultures (A) or substantial demyelination in companion cultures after 3 d of treatment with 200 ng/ml GGF. The mean percentage of damaged myelin sheaths in the cultures treated with GGF for 2 d was significantly higher than that in control cultures (P < 0.0001) (C). The mean values and SEM presented for each GGF concentration are from 12 random fields pooled from a representative experiment. Bar, 100 μm.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2199210&req=5

Figure 3: GGF causes demyelination. Immunofluorescence micrographs of cocultures that had myelinated for 3 wk demonstrating normal myelination in control cultures (A) or substantial demyelination in companion cultures after 3 d of treatment with 200 ng/ml GGF. The mean percentage of damaged myelin sheaths in the cultures treated with GGF for 2 d was significantly higher than that in control cultures (P < 0.0001) (C). The mean values and SEM presented for each GGF concentration are from 12 random fields pooled from a representative experiment. Bar, 100 μm.

Mentions: We next analyzed the effects of GGF on cocultures in which myelin had already formed. Treatment of established, myelinated cocultures with GGF for 2 or 3 d resulted in striking demyelination. Fig. 3 A shows an immunofluorescence micrograph of a representative field from a myelinated coculture, and B shows another coculture undergoing substantial demyelination after 3 d of continuous treatment with 200 ng/ml of GGF. The demyelinating effects of GGF were dose dependent (Fig. 3 C). Significant demyelination was observed with 2 d of treatment even at 20 ng/ml; more extensive demyelination was evident at higher concentrations. At GGF concentrations of 200 ng/ml, ∼75% of the myelin sheaths degenerated; the remaining sheaths displayed no obvious morphological defects. While this effect was most robust with continuous treatment, nearly comparable demyelination was observed after only 30 min of GGF treatment followed by its removal (data not shown). Finally, treatment with either FGF-2 (10 and 100 ng/ml) or TGF-β1 (10 and 100 ng/ml) did not induce obvious myelin sheath degeneration, indicating this effect was specific to the neuregulins (data not shown).


Glial growth factor/neuregulin inhibits Schwann cell myelination and induces demyelination.

Zanazzi G, Einheber S, Westreich R, Hannocks MJ, Bedell-Hogan D, Marchionni MA, Salzer JL - J. Cell Biol. (2001)

GGF causes demyelination. Immunofluorescence micrographs of cocultures that had myelinated for 3 wk demonstrating normal myelination in control cultures (A) or substantial demyelination in companion cultures after 3 d of treatment with 200 ng/ml GGF. The mean percentage of damaged myelin sheaths in the cultures treated with GGF for 2 d was significantly higher than that in control cultures (P < 0.0001) (C). The mean values and SEM presented for each GGF concentration are from 12 random fields pooled from a representative experiment. Bar, 100 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199210&req=5

Figure 3: GGF causes demyelination. Immunofluorescence micrographs of cocultures that had myelinated for 3 wk demonstrating normal myelination in control cultures (A) or substantial demyelination in companion cultures after 3 d of treatment with 200 ng/ml GGF. The mean percentage of damaged myelin sheaths in the cultures treated with GGF for 2 d was significantly higher than that in control cultures (P < 0.0001) (C). The mean values and SEM presented for each GGF concentration are from 12 random fields pooled from a representative experiment. Bar, 100 μm.
Mentions: We next analyzed the effects of GGF on cocultures in which myelin had already formed. Treatment of established, myelinated cocultures with GGF for 2 or 3 d resulted in striking demyelination. Fig. 3 A shows an immunofluorescence micrograph of a representative field from a myelinated coculture, and B shows another coculture undergoing substantial demyelination after 3 d of continuous treatment with 200 ng/ml of GGF. The demyelinating effects of GGF were dose dependent (Fig. 3 C). Significant demyelination was observed with 2 d of treatment even at 20 ng/ml; more extensive demyelination was evident at higher concentrations. At GGF concentrations of 200 ng/ml, ∼75% of the myelin sheaths degenerated; the remaining sheaths displayed no obvious morphological defects. While this effect was most robust with continuous treatment, nearly comparable demyelination was observed after only 30 min of GGF treatment followed by its removal (data not shown). Finally, treatment with either FGF-2 (10 and 100 ng/ml) or TGF-β1 (10 and 100 ng/ml) did not induce obvious myelin sheath degeneration, indicating this effect was specific to the neuregulins (data not shown).

Bottom Line: Glial growth factor (GGF), a neuregulin-1 isoform, significantly inhibited myelination by preventing axonal segregation and ensheathment.Two other Schwann cell mitogens, fibroblast growth factor-2 and transforming growth factor-beta, inhibited myelination but did not cause demyelination, suggesting this effect is specific to the neuregulins.GGF treatment of myelinating cultures also induced phosphorylation of phosphatidylinositol 3-kinase, mitogen-activated protein kinase, and a 120-kD protein.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, New York University Medical Center, New York, New York 10016, USA.

ABSTRACT
During development, neuregulin-1 promotes Schwann cell proliferation and survival; its role in later events of Schwann cell differentiation, including myelination, is poorly understood. Accordingly, we have examined the effects of neuregulin-1 on myelination in neuron-Schwann cell cocultures. Glial growth factor (GGF), a neuregulin-1 isoform, significantly inhibited myelination by preventing axonal segregation and ensheathment. Basal lamina formation was not affected. Treatment of established myelinated cultures with GGF resulted in striking demyelination that frequently began at the paranodes and progressed to the internode. Demyelination was dose dependent and accompanied by dedifferentiation of Schwann cells to a promyelinating stage, as evidenced by reexpression of the transcription factor suppressed cAMP-inducible POU; a significant proportion of cells with extensive demyelination also proliferated. Two other Schwann cell mitogens, fibroblast growth factor-2 and transforming growth factor-beta, inhibited myelination but did not cause demyelination, suggesting this effect is specific to the neuregulins. The neuregulin receptor proteins, erbB2 and erbB3, are expressed on ensheathing and myelinating Schwann cells and rapidly phosphorylated with GGF treatment. GGF treatment of myelinating cultures also induced phosphorylation of phosphatidylinositol 3-kinase, mitogen-activated protein kinase, and a 120-kD protein. These results suggest that neuronal mitogens, including the neuregulins, may inhibit myelination during development and that activation of mitogen signaling pathways may contribute to the initial demyelination and subsequent Schwann cell proliferation observed in various pathologic conditions.

Show MeSH
Related in: MedlinePlus