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Axonal neuregulin signals cells of the oligodendrocyte lineage through activation of HER4 and Schwann cells through HER2 and HER3.

Vartanian T, Goodearl A, Viehöver A, Fischbach G - J. Cell Biol. (1997)

Bottom Line: We have found that oligodendrocite-type II astrocyte (O2A) progenitor cells and mature oligodendrocytes express HER2 and HER4 but no HER3.Coimmunoprecipitation experiments indicate that receptor activation in Schwann cells results in the formation of HER2:HER3 heterodimers.The use of unique neuregulin receptor combinations in oligodendrocytes and Schwann cells likely results in recruitment of different signaling pathways and thus provides a basis for different biological responses.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.

ABSTRACT
We are interested in the signaling between axons and glia that leads to myelination and maintenance of the myelin internode, and we have focused on the role of neuregulins and their receptors. Neuregulins are a family of ligands that includes heregulin, neu differentiation factor, glial growth factor, and the acetylcholine receptor-inducing activity. Three signal transducing transmembrane receptors for neuregulins, which bear significant homology to the EGF receptor, are currently known: HER2 (erbB2), HER3 (erbB3), and HER4 (erbB4). We have found that oligodendrocite-type II astrocyte (O2A) progenitor cells and mature oligodendrocytes express HER2 and HER4 but no HER3. Schwann cells express HER2 and HER3 but little HER4. In O2A progenitor cells and oligodendrocytes, recombinant neuregulin induces the rapid tyrosine phosphorylation of only HER4. HER2 is not phosphorylated in cells of the oligodendrocyte lineage, but a physical interaction between HER2 and HER4 was detected in coimmunoprecipitation experiments. In Schwann cells, neuregulin induces the phosphorylation of both HER2 and HER3. Coimmunoprecipitation experiments indicate that receptor activation in Schwann cells results in the formation of HER2:HER3 heterodimers. Neuregulin localized immunocytochemically was present on neurites of cultured dorsal root ganglion neurons, and it was released into the medium in a form that promoted receptor tyrosine phosphorylation. Neuregulins therefore meet important criteria expected of molecules involved in axonal-glial signaling. The use of unique neuregulin receptor combinations in oligodendrocytes and Schwann cells likely results in recruitment of different signaling pathways and thus provides a basis for different biological responses.

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Neuregulin from DRG neurons is biologically active.  Conditioned medium isolated from two separate cultures of DRG  neurons (DRG CM 1 and 2) and membrane vesicles from DRG  neurons were prepared as described and studied for their ability  to induce tyrosine phosphorylation of p185 in L6 cells. L6 cells  were incubated with conditioned medium for 30 min and then  harvested in SDS-loading buffer with β-mercaptoethanol. Lysates were resolved on 5% polyacrylamide gels, and proteins  were transferred to PVDF membranes that were probed with antiphosphotyrosine antibodies. p185 phosphorylation is evident in  L6 cells treated with DRG-conditioned medium, EGFβ1-like domain of neu differentiation factor, and recombinant acetylcholine  receptor–inducing activity, but not control medium or fibroblast  conditioned medium.
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Figure 8: Neuregulin from DRG neurons is biologically active. Conditioned medium isolated from two separate cultures of DRG neurons (DRG CM 1 and 2) and membrane vesicles from DRG neurons were prepared as described and studied for their ability to induce tyrosine phosphorylation of p185 in L6 cells. L6 cells were incubated with conditioned medium for 30 min and then harvested in SDS-loading buffer with β-mercaptoethanol. Lysates were resolved on 5% polyacrylamide gels, and proteins were transferred to PVDF membranes that were probed with antiphosphotyrosine antibodies. p185 phosphorylation is evident in L6 cells treated with DRG-conditioned medium, EGFβ1-like domain of neu differentiation factor, and recombinant acetylcholine receptor–inducing activity, but not control medium or fibroblast conditioned medium.

Mentions: Both neuregulin secreted into the medium and that associated with the cell surface possess biological activity. Concentrated conditioned medium and a preparation of cell membranes from sensory neuron cultures were tested for p185 (neuregulin receptor) tyrosine phosphorylation using L6 muscle cells, which express high levels of neuregulin receptors. The conditioned medium samples stimulated significant p185 phosphorylation, confirming that active neuregulins are released by sensory neurons in culture (Fig. 8). Furthermore, the DRG cell membranes were also positive in this assay, demonstrating that surface bound neuregulins are able to play a role in signaling (Fig. 8).


Axonal neuregulin signals cells of the oligodendrocyte lineage through activation of HER4 and Schwann cells through HER2 and HER3.

Vartanian T, Goodearl A, Viehöver A, Fischbach G - J. Cell Biol. (1997)

Neuregulin from DRG neurons is biologically active.  Conditioned medium isolated from two separate cultures of DRG  neurons (DRG CM 1 and 2) and membrane vesicles from DRG  neurons were prepared as described and studied for their ability  to induce tyrosine phosphorylation of p185 in L6 cells. L6 cells  were incubated with conditioned medium for 30 min and then  harvested in SDS-loading buffer with β-mercaptoethanol. Lysates were resolved on 5% polyacrylamide gels, and proteins  were transferred to PVDF membranes that were probed with antiphosphotyrosine antibodies. p185 phosphorylation is evident in  L6 cells treated with DRG-conditioned medium, EGFβ1-like domain of neu differentiation factor, and recombinant acetylcholine  receptor–inducing activity, but not control medium or fibroblast  conditioned medium.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2139859&req=5

Figure 8: Neuregulin from DRG neurons is biologically active. Conditioned medium isolated from two separate cultures of DRG neurons (DRG CM 1 and 2) and membrane vesicles from DRG neurons were prepared as described and studied for their ability to induce tyrosine phosphorylation of p185 in L6 cells. L6 cells were incubated with conditioned medium for 30 min and then harvested in SDS-loading buffer with β-mercaptoethanol. Lysates were resolved on 5% polyacrylamide gels, and proteins were transferred to PVDF membranes that were probed with antiphosphotyrosine antibodies. p185 phosphorylation is evident in L6 cells treated with DRG-conditioned medium, EGFβ1-like domain of neu differentiation factor, and recombinant acetylcholine receptor–inducing activity, but not control medium or fibroblast conditioned medium.
Mentions: Both neuregulin secreted into the medium and that associated with the cell surface possess biological activity. Concentrated conditioned medium and a preparation of cell membranes from sensory neuron cultures were tested for p185 (neuregulin receptor) tyrosine phosphorylation using L6 muscle cells, which express high levels of neuregulin receptors. The conditioned medium samples stimulated significant p185 phosphorylation, confirming that active neuregulins are released by sensory neurons in culture (Fig. 8). Furthermore, the DRG cell membranes were also positive in this assay, demonstrating that surface bound neuregulins are able to play a role in signaling (Fig. 8).

Bottom Line: We have found that oligodendrocite-type II astrocyte (O2A) progenitor cells and mature oligodendrocytes express HER2 and HER4 but no HER3.Coimmunoprecipitation experiments indicate that receptor activation in Schwann cells results in the formation of HER2:HER3 heterodimers.The use of unique neuregulin receptor combinations in oligodendrocytes and Schwann cells likely results in recruitment of different signaling pathways and thus provides a basis for different biological responses.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.

ABSTRACT
We are interested in the signaling between axons and glia that leads to myelination and maintenance of the myelin internode, and we have focused on the role of neuregulins and their receptors. Neuregulins are a family of ligands that includes heregulin, neu differentiation factor, glial growth factor, and the acetylcholine receptor-inducing activity. Three signal transducing transmembrane receptors for neuregulins, which bear significant homology to the EGF receptor, are currently known: HER2 (erbB2), HER3 (erbB3), and HER4 (erbB4). We have found that oligodendrocite-type II astrocyte (O2A) progenitor cells and mature oligodendrocytes express HER2 and HER4 but no HER3. Schwann cells express HER2 and HER3 but little HER4. In O2A progenitor cells and oligodendrocytes, recombinant neuregulin induces the rapid tyrosine phosphorylation of only HER4. HER2 is not phosphorylated in cells of the oligodendrocyte lineage, but a physical interaction between HER2 and HER4 was detected in coimmunoprecipitation experiments. In Schwann cells, neuregulin induces the phosphorylation of both HER2 and HER3. Coimmunoprecipitation experiments indicate that receptor activation in Schwann cells results in the formation of HER2:HER3 heterodimers. Neuregulin localized immunocytochemically was present on neurites of cultured dorsal root ganglion neurons, and it was released into the medium in a form that promoted receptor tyrosine phosphorylation. Neuregulins therefore meet important criteria expected of molecules involved in axonal-glial signaling. The use of unique neuregulin receptor combinations in oligodendrocytes and Schwann cells likely results in recruitment of different signaling pathways and thus provides a basis for different biological responses.

Show MeSH
Related in: MedlinePlus