Limits...
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.

Show MeSH
HER2 and HER3 are present on Schwann cells. Schwann cells were cultured as described, fixed in 4% paraformaldehyde,  permeabilized with 0.125% Triton X-100, and stained with polyclonal antisera directed against HER2 or HER3 followed by Cy3-conjugated secondary antibodies. Virtually all Schwann cells stain for both HER2 and HER3. Bar, 50 μm.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2139859&req=5

Figure 4: HER2 and HER3 are present on Schwann cells. Schwann cells were cultured as described, fixed in 4% paraformaldehyde, permeabilized with 0.125% Triton X-100, and stained with polyclonal antisera directed against HER2 or HER3 followed by Cy3-conjugated secondary antibodies. Virtually all Schwann cells stain for both HER2 and HER3. Bar, 50 μm.

Mentions: Neuregulin receptor expression by O2A progenitor cells and oligodendrocytes was evaluated by immunohistochemistry and Western blotting. O2A progenitor cells isolated from P0 rat forebrain were grown in serum-free, chemically defined medium (see Materials and Methods) in the presence of PDGF-AA and basic FGF to maintain cells as a proliferating progenitor cell population (18, 41, 72), or in the absence of these mitogens and in the presence of insulin to allow for differentiation into oligodendrocytes. Both O2A progenitor cells and oligodendrocytes stained with antibodies directed against HER2 and HER4 (Fig. 1) but not HER3 (not shown). The affinity of the HER3 antibody was adequate for immunohistochemistry as demonstrated with Schwann cell staining (see Fig. 4). Specificity of the HER2 and HER4 antibodies was shown by blocking with an excess of peptide from which the antibodies were raised (Fig. 1). 100% of O2A progenitor cells and oligodendrocytes stain for HER2 or HER4 in single labeling studies, and thus we infer that individual O2A progenitor cells and oligodendrocytes possess both HER2 and HER4. The staining pattern in O2A progenitor cells was similar but not identical for HER2 and HER4. HER2 immunoreactivity was present throughout the entire length of the bipolar processes in O2A progenitor cells, while HER4 immunoreactivity was absent in the distal-most ends of processes.


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)

HER2 and HER3 are present on Schwann cells. Schwann cells were cultured as described, fixed in 4% paraformaldehyde,  permeabilized with 0.125% Triton X-100, and stained with polyclonal antisera directed against HER2 or HER3 followed by Cy3-conjugated secondary antibodies. Virtually all Schwann cells stain for both HER2 and HER3. Bar, 50 μm.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 4: HER2 and HER3 are present on Schwann cells. Schwann cells were cultured as described, fixed in 4% paraformaldehyde, permeabilized with 0.125% Triton X-100, and stained with polyclonal antisera directed against HER2 or HER3 followed by Cy3-conjugated secondary antibodies. Virtually all Schwann cells stain for both HER2 and HER3. Bar, 50 μm.
Mentions: Neuregulin receptor expression by O2A progenitor cells and oligodendrocytes was evaluated by immunohistochemistry and Western blotting. O2A progenitor cells isolated from P0 rat forebrain were grown in serum-free, chemically defined medium (see Materials and Methods) in the presence of PDGF-AA and basic FGF to maintain cells as a proliferating progenitor cell population (18, 41, 72), or in the absence of these mitogens and in the presence of insulin to allow for differentiation into oligodendrocytes. Both O2A progenitor cells and oligodendrocytes stained with antibodies directed against HER2 and HER4 (Fig. 1) but not HER3 (not shown). The affinity of the HER3 antibody was adequate for immunohistochemistry as demonstrated with Schwann cell staining (see Fig. 4). Specificity of the HER2 and HER4 antibodies was shown by blocking with an excess of peptide from which the antibodies were raised (Fig. 1). 100% of O2A progenitor cells and oligodendrocytes stain for HER2 or HER4 in single labeling studies, and thus we infer that individual O2A progenitor cells and oligodendrocytes possess both HER2 and HER4. The staining pattern in O2A progenitor cells was similar but not identical for HER2 and HER4. HER2 immunoreactivity was present throughout the entire length of the bipolar processes in O2A progenitor cells, while HER4 immunoreactivity was absent in the distal-most ends of processes.

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