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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.
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