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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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Demyelination and proliferation are not obligately linked. Myelinated cocultures were incubated with BrdU for 36 h in media without (A and B) or with (C and D) 200 ng/ml GGF. The cocultures were then fixed and stained for BrdU (green) and MBP (red); nuclei are stained with Hoechst (blue). In control cultures, myelinating Schwann cells do not incorporate BrdU (four representative nuclei are encircled in A and B), whereas BrdU-positive nuclei are relatively common in GGF-treated cultures, typically in cells undergoing extensive demyelination (C, arrowhead and inset). Note also that the nuclei of several degenerating myelin sheaths are BrdU− (*). This increase in BrdU labeling was associated with actual Schwann cell mitosis as BrdU+ nuclei were also present as doublets (C, inset). Bar, 40 μm.
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Figure 6: Demyelination and proliferation are not obligately linked. Myelinated cocultures were incubated with BrdU for 36 h in media without (A and B) or with (C and D) 200 ng/ml GGF. The cocultures were then fixed and stained for BrdU (green) and MBP (red); nuclei are stained with Hoechst (blue). In control cultures, myelinating Schwann cells do not incorporate BrdU (four representative nuclei are encircled in A and B), whereas BrdU-positive nuclei are relatively common in GGF-treated cultures, typically in cells undergoing extensive demyelination (C, arrowhead and inset). Note also that the nuclei of several degenerating myelin sheaths are BrdU− (*). This increase in BrdU labeling was associated with actual Schwann cell mitosis as BrdU+ nuclei were also present as doublets (C, inset). Bar, 40 μm.

Mentions: GGF induced a significant, approximately fourfold increase in the overall rate of Schwann cell proliferation, which is normally quite low in these mature cultures (i.e., from 1.4 to 6.4% after 36 h of BrdU incorporation). When MBP+ Schwann cells were analyzed, the mitogenic effects of GGF depended on the extent of demyelination. A small percentage of Schwann cells with apparently intact myelin sheaths were BrdU+ in the treated cultures. As myelinating Schwann cells normally do not proliferate (Salzer and Bunge 1980; see also Fig. 6 A), a labeling index of 3% in such cells is significant. These results indicate that proliferation of myelinating Schwann cells can occur in the absence of obvious demyelination. Cells with myelin sheaths in late stages of degeneration proliferated the most extensively in response to GGF treatment, exhibiting a labeling index of 27%; several examples are shown in Fig. 6 C. Strikingly, most Schwann cells, even those with significant myelin degeneration, did not proliferate during the 36-h treatment period; thus, 97% of cells with moderate and 73% of those with advanced myelin sheath degeneration remained unlabeled (Table ). The latter results indicate that GGF-induced demyelination does not require Schwann cells to re-enter the cell cycle. After 48 h of GGF treatment, demyelination was more extensive and the labeling index increased to ∼50% in those cells with extensive myelin sheath degeneration. Even at this later time point, however, many Schwann cells with substantial demyelination were unlabeled. Taken together, these studies indicate that demyelination does not require Schwann cell proliferation and that proliferation typically occurs when demyelination is quite advanced.


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)

Demyelination and proliferation are not obligately linked. Myelinated cocultures were incubated with BrdU for 36 h in media without (A and B) or with (C and D) 200 ng/ml GGF. The cocultures were then fixed and stained for BrdU (green) and MBP (red); nuclei are stained with Hoechst (blue). In control cultures, myelinating Schwann cells do not incorporate BrdU (four representative nuclei are encircled in A and B), whereas BrdU-positive nuclei are relatively common in GGF-treated cultures, typically in cells undergoing extensive demyelination (C, arrowhead and inset). Note also that the nuclei of several degenerating myelin sheaths are BrdU− (*). This increase in BrdU labeling was associated with actual Schwann cell mitosis as BrdU+ nuclei were also present as doublets (C, inset). Bar, 40 μm.
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Related In: Results  -  Collection

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Figure 6: Demyelination and proliferation are not obligately linked. Myelinated cocultures were incubated with BrdU for 36 h in media without (A and B) or with (C and D) 200 ng/ml GGF. The cocultures were then fixed and stained for BrdU (green) and MBP (red); nuclei are stained with Hoechst (blue). In control cultures, myelinating Schwann cells do not incorporate BrdU (four representative nuclei are encircled in A and B), whereas BrdU-positive nuclei are relatively common in GGF-treated cultures, typically in cells undergoing extensive demyelination (C, arrowhead and inset). Note also that the nuclei of several degenerating myelin sheaths are BrdU− (*). This increase in BrdU labeling was associated with actual Schwann cell mitosis as BrdU+ nuclei were also present as doublets (C, inset). Bar, 40 μm.
Mentions: GGF induced a significant, approximately fourfold increase in the overall rate of Schwann cell proliferation, which is normally quite low in these mature cultures (i.e., from 1.4 to 6.4% after 36 h of BrdU incorporation). When MBP+ Schwann cells were analyzed, the mitogenic effects of GGF depended on the extent of demyelination. A small percentage of Schwann cells with apparently intact myelin sheaths were BrdU+ in the treated cultures. As myelinating Schwann cells normally do not proliferate (Salzer and Bunge 1980; see also Fig. 6 A), a labeling index of 3% in such cells is significant. These results indicate that proliferation of myelinating Schwann cells can occur in the absence of obvious demyelination. Cells with myelin sheaths in late stages of degeneration proliferated the most extensively in response to GGF treatment, exhibiting a labeling index of 27%; several examples are shown in Fig. 6 C. Strikingly, most Schwann cells, even those with significant myelin degeneration, did not proliferate during the 36-h treatment period; thus, 97% of cells with moderate and 73% of those with advanced myelin sheath degeneration remained unlabeled (Table ). The latter results indicate that GGF-induced demyelination does not require Schwann cells to re-enter the cell cycle. After 48 h of GGF treatment, demyelination was more extensive and the labeling index increased to ∼50% in those cells with extensive myelin sheath degeneration. Even at this later time point, however, many Schwann cells with substantial demyelination were unlabeled. Taken together, these studies indicate that demyelination does not require Schwann cell proliferation and that proliferation typically occurs when demyelination is quite advanced.

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