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

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.

Specification of Optic Nerve Oligodendrocyte Precursors by Retinal Ganglion Cell Axons

“…Our studies suggest that, although both Shh and NRG are required for the appearance of optic nerve OPCs, they may not be sufficient for the commitment of neural epithelial cells to the oligodendrocyte lineage. For example, retinal conditioned medium effectively induces OPCs in dorsal spinal cord cultures, whereas the addition of soluble Shh or NRG singly or in combination does not, although they are functional in other systems (Vartanian et al, 1997). It may be either that additional molecules such as neurotransmitters like glutamate (Yuan et al, 1998) are released by retinal cells or that the ligands have to be presented to responsive cells in a precise manner.…”

Aberrant motor axon projection, acetylcholine receptor clustering, and neurotransmission in cyclin-dependent kinase 5 null mice

“…4H), suggesting that the lack of S100 staining in Cdk5 Ϫ/Ϫ phrenic nerves was likely due to the loss of Schwann cells. Interestingly, the morphology and functions of these Schwann cells and their expression profiles of ErbB receptors are quite different from terminal Schwann cells (18,28,31). It is possible that the absence of defects in terminal Schwann cells of Cdk5 Ϫ/Ϫ embryos is, in part, because of their differential requirement of NRG͞ErbB signaling.…”

“…Schwann cells were purified from the sciatic nerve of postnatal day 1 rats, as described in ref. 18. For survival assay, the cells were fixed and labeled by using TUNEL assay (Promega) and Hoechst 33342 (Sigma), as described in ref.…”

Glial Growth Factor Rescues Schwann Cells of Mechanoreceptors from Denervation-Induced Apoptosis

“…The specificity of staining for each antibody was confirmed by its elimination after incubation with the appropriate control peptide. Interestingly, erbB4 has not been detected in Schwann cells that are not associated with mechanoreceptors (Grinspan et al, 1996;Carroll et al, 1997), except in one recent study (Vartanian et al, 1997) in which trace amounts of erbB4 were detected in cultured rat Schwann cells by Western blotting. In addition, message to erbB4 was detected in human Schwann cells (Levi et al, 1995).…”