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© The Rockefeller University Press, 0021-9525/1997//211 $5.00
The Journal of Cell Biology, Volume 137, Number 1, , 1997 211-220

Article

Axonal Neuregulin Signals Cells of the Oligodendrocyte Lineage through Activation of HER4 and Schwann Cells through HER2 and HER3



Timothy Vartanian, Andrew Goodearl, Andrea Viehöver, and Gerald Fischbach

Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115

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.

Abbreviations used in this paper: CNS and PNS, central and peripheral nervous systems; DRG, dorsal root ganglion; E, embryonic day; EGFR, epidermal growth factor receptor; GGF, glial growth factor; O2A, oligodendrocyte–type II astrocyte; P, postnatal day; PVDF, polyvinyl difluoride.

We would like to acknowledge the late Dr. Richard Bunge, who was a pioneer in the fields of Schwann cell biology and axonal glial interactions, and whose contributions form a firm base upon which our current experiments are built. The authors also thank Amgen Biologicals (Thousand Oaks, CA) for providing the recombinant EGFβ1 domain of neuregulin.

Address all correspondence to Dr. Timothy Vartanian, Department of Neurobiology, Harvard Medical School, WAB 328, 200 Longwood Avenue, Boston, MA 02115.


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