Nrg1/ErbB signaling networks in Schwann cell development and myelination

Abstract

Neuregulin-1 (Nrg1) provides a key axonal signal that regulates Schwann cell proliferation, migration and myelination through binding to ErbB2/3 receptors. The analysis of a number of genetic models has unmasked fundamental mechanisms underlying the specificity of the Nrg1/ErbB signaling axis. Differential expression of Nrg1 isoforms, Nrg1 processing, and ErbB receptor localization and trafficking represent important regulatory themes in the control of Nrg1/ErbB function. Nrg1 binding to ErbB2/3 receptors results in the activation of intracellular signal transduction pathways that initiate changes in Schwann cell behavior. Here, we review data that has defined the role of key Nrg1/ErbB signaling components like Shp2, ERK1/2, FAK, Rac1/Cdc42 and calcineurin in development of the Schwann cell lineage in vivo. Many of these regulators receive converging signals from other cues that are provided by Notch, integrin or G-protein coupled receptors. Signaling by multiple extracellular factors may act as key modifiers and allow Schwann cells at different developmental stages to respond in distinct manners to the Nrg1/ErbB signal.

Figure 1. Nrg1/ErbB signaling

Following Nrg1 binding, heteromeric ErbB2/3 receptors auto- and trans-phosphorylate specific tyrosine residues, and to these phosphorylated residues specific adaptor proteins and enzymes are recruited. This results in the activation of a number of downstream signaling pathways, including PI3K/Akt, Erk1/2, FAK, and Rac/Cdc42, and Ca2⁺ regulated pathways downstream of PLCγ lead to activation of calcineurin. Shp2 and Src are thought to regulate Erk1/2 signaling by modulating Ras, although other mechanisms also have been observed. These pathways regulate the activity of cytoplasmic and nuclear signal transduction molecules that mediate specific Schwann cell responses to the Nrg1 signal.

Figure 2. Hypomyelination of ErbB2 and Shp2 mutant peripheral nerves

Electron microscopic analysis of peripheral nerves from control mice (A), and from mice that carry Schwann cell-specific mutations of ErbB2 (B) or Shp2 (C) that were introduced using a Krox20cre allele. Note that the conditional ErbB2 and Shp2 mutant mice display a marked hypomyelination in the adult. (D) Quantification of myelin thickness in adult control (blue bars), conditional ErbB2 (red bars) and Shp2 (yellow bars) mutant mice. Displayed is a plot of the myelin thickness versus axon diameter. Note the similarity of the effects of the ErbB2 and Shp2 mutations.

Figure 3

Nrg1/ErbB signaling acts cooperatively with other extracellular cues to control myelination. Amongst many potentially important ligand/receptor complexes, key roles have been attributed to laminin/integrin and Gpr126 signaling in Schwann cell myelination in vivo.