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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.

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Ultrastructure of control and GGF-treated cocultures. Schwann cell-DRG neuron cocultures that had myelinated for 3 wk were maintained for an additional 3 d without (A) or with (B and C) 200 ng/ml GGF. The cocultures were then fixed and processed for electron microscopy. (A) Longitudinal section through a control internode, (B) sections of two Schwann cells; note the presence of numerous myelin inclusions (arrows). (C) Section through a paranode that contains a myelin inclusion (arrow) and an abnormal folding of the myelin sheath. Bars, 0.2 μm.
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Figure 4: Ultrastructure of control and GGF-treated cocultures. Schwann cell-DRG neuron cocultures that had myelinated for 3 wk were maintained for an additional 3 d without (A) or with (B and C) 200 ng/ml GGF. The cocultures were then fixed and processed for electron microscopy. (A) Longitudinal section through a control internode, (B) sections of two Schwann cells; note the presence of numerous myelin inclusions (arrows). (C) Section through a paranode that contains a myelin inclusion (arrow) and an abnormal folding of the myelin sheath. Bars, 0.2 μm.

Mentions: Fibers undergoing demyelination were initially characterized by crenated myelin sheaths followed by overt myelin breakdown and ovoid formation. Degeneration of some myelin sheaths was already apparent after 24 h of treatment, but in most cases maximal demyelination occurred between 36 and 48 h of treatment. Myelin debris was then rapidly cleared and, by 72 h, was substantially absent from the cultures. Demyelination often began at one end of the myelin sheath, progressing from the paranodal region to the Schwann cell internode (data not shown). To analyze this effect further, control and treated cultures were examined by electron microscopy (Fig. 4). In general, we observed significant amounts of myelin debris within myelin segments. Some of these appeared to be present within vacuoles; they were present both in the internode and the paranodal region (Fig. 4 C). These results suggest that Schwann cells are able to clear segments of the myelin sheath while other regions remain remarkably intact.


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)

Ultrastructure of control and GGF-treated cocultures. Schwann cell-DRG neuron cocultures that had myelinated for 3 wk were maintained for an additional 3 d without (A) or with (B and C) 200 ng/ml GGF. The cocultures were then fixed and processed for electron microscopy. (A) Longitudinal section through a control internode, (B) sections of two Schwann cells; note the presence of numerous myelin inclusions (arrows). (C) Section through a paranode that contains a myelin inclusion (arrow) and an abnormal folding of the myelin sheath. Bars, 0.2 μm.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2199210&req=5

Figure 4: Ultrastructure of control and GGF-treated cocultures. Schwann cell-DRG neuron cocultures that had myelinated for 3 wk were maintained for an additional 3 d without (A) or with (B and C) 200 ng/ml GGF. The cocultures were then fixed and processed for electron microscopy. (A) Longitudinal section through a control internode, (B) sections of two Schwann cells; note the presence of numerous myelin inclusions (arrows). (C) Section through a paranode that contains a myelin inclusion (arrow) and an abnormal folding of the myelin sheath. Bars, 0.2 μm.
Mentions: Fibers undergoing demyelination were initially characterized by crenated myelin sheaths followed by overt myelin breakdown and ovoid formation. Degeneration of some myelin sheaths was already apparent after 24 h of treatment, but in most cases maximal demyelination occurred between 36 and 48 h of treatment. Myelin debris was then rapidly cleared and, by 72 h, was substantially absent from the cultures. Demyelination often began at one end of the myelin sheath, progressing from the paranodal region to the Schwann cell internode (data not shown). To analyze this effect further, control and treated cultures were examined by electron microscopy (Fig. 4). In general, we observed significant amounts of myelin debris within myelin segments. Some of these appeared to be present within vacuoles; they were present both in the internode and the paranodal region (Fig. 4 C). These results suggest that Schwann cells are able to clear segments of the myelin sheath while other regions remain remarkably intact.

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