Membrane-Bound Neuregulin1 Type III Actively Promotes Schwann Cell Differentiation of Multipotent Progenitor Cells

Abstract

Many steps of peripheral glia development appear to be regulated by neuregulin1 (NRG1) signaling but the exact roles of the different NRG1 isoforms in these processes remain to be determined. While glial growth factor 2 (GGF2), a NRG1 type II isoform, is able to induce a satellite glial fate in neural crest stem cells, targeted mutations in mice have revealed a prominent role of NRG1 type III isoforms in supporting survival of Schwann cells at early developmental stages. Here, we investigated the role of NRG1 isoforms in the differentiation of Schwann cells from neural crest-derived progenitor cells. In multipotent cells isolated from dorsal root ganglia, soluble NRG1 isoforms do not promote Schwann cell features, whereas signaling by membrane-associated NRG1 type III induces the expression of the Schwann cell markers Oct-6/SCIP and S100 in neighboring cells, independent of survival. Thus, axon-bound NRG1 might actively promote both Schwann cell survival and differentiation.

Axonal Neuregulin 1 Type III Activates NF-κB in Schwann Cells during Myelin Formation

“…Activity-Axons express type III NRG1 (14,25,26), and our results demonstrate that this specific isoform, when expressed in COS7 cells, can activate NF-B (Fig. 2A).…”

“…these results suggest that axonal NRG1 type III stimulation of ErbB2/3 receptors on Schwann cells results in the activation of NF-B. (14,25,26), this growth factor is also known to promote Schwann cell proliferation (18). In addition, activation of NF-B can stimulate cell proliferation in some contexts (38).…”

“…NRG1 Type III, but Not Other NRG1 Isoforms, Stimulates NF-B-NRG1 type III is expressed on the surface of axons and known to be essential for Schwann cell development and myelin formation (14,16,18,(23)(24)(25)(26). Furthermore, the neuregulin receptor ErbB2, activated in breast cancer cells, has been shown to stimulate NF-B (27).…”

Neuregulin-1 modulates the differentiation of neural stem cells in vitro trough an interaction with the Swi/Snf complex

“…Among growth factors that could modulate nervous system development, neuregulins (NRG) constitute a specialized family of growth factors, which are better known as regulators of various aspects of the nervous system biology (Adlkofer and Lai, 2000;Leimeroth et al, 2002;Lai and Feng, 2004). Each isoform of neuregulin contains an extracellular EGF-like motif, the hallmark of the neuregulin family, which consists of four genes: Nrg-1 (Britsch, 2007), Nrg-2 (Carraway et al, 1997;Chang et al, 1997), Nrg-3 (Hijazi et al, 1998;Zhang et al, 1997) and Nrg-4 (Harari et al, 1999).…”

“…Indeed, Nrg-1-encoded proteins promote proliferation, differentiation and myelination of Schwann cells (Leimeroth et al, 2002) and oligodendrocytes (Raabe et al, 1996). They also promote maturation and survival of astrocytes (Pinkas-Kramarski et al, 1994).…”