Schwann cell development, maturation and regeneration: a focus on classic and emerging intracellular signaling pathways

Abstract

The development, maturation and regeneration of Schwann cells (SCs), the main glial cells of the peripheral nervous system, require the coordinate and complementary interaction among several factors, signals and intracellular pathways. These regulatory molecules consist of integrins, neuregulins, growth factors, hormones, neurotransmitters, as well as entire intracellular pathways including protein-kinase A, C, Akt, Erk/MAPK, Hippo, mTOR, etc. For instance, Hippo pathway is overall involved in proliferation, apoptosis, regeneration and organ size control, being crucial in cancer proliferation process. In SCs, Hippo is linked to merlin and YAP/TAZ signaling and it seems to respond to mechanic/physical challenges. Recently, among factors regulating SCs, also the signaling intermediates Src tyrosine kinase and focal adhesion kinase (FAK) proved relevant for SC fate, participating in the regulation of adhesion, motility, migration and in vitro myelination. In SCs, the factors Src and FAK are regulated by the neuroactive steroid allopregnanolone, thus corroborating the importance of this steroid in the control of SC maturation. In this review, we illustrate some old and novel signaling pathways modulating SC biology and functions during the different developmental, mature and regenerative states.

Keywords: electromagnetic field; myelin; neuroactive steroids; peripheral nervous system.

Figure 1

Scheme of development, maturation and repairing of Schwann cells (SCs). SC development begins with neural crest cells (panel A). They later develop into SC precursors (panel B) then into immature SCs, which start the radial sorting process (panel C). After radial sorting, SCs alternatively mature into pro-myelinating SCs, which originate myelinating SCs, or into non-myelinating SCs, which form Remak bundles. Mature SCs are characterized by remarkable plasticity, since following injury, they can differentiate into repairing SCs (panel D).

Figure 2

Scheme of some intracellular pathways involving FAK, cdc42, rac1, Src and merlin, in Schwann cell (SC) development, radial sorting, myelination and nerve repair. Firstly, during the PNS development, the interaction of SCs with the extracellular matrix can phosphorylate FAK, activate cdc42, then phosphorylate merlin, determining the SC multipolar morphology and radial sorting process (panel A). Later, during the myelination onset, this phosphorylation cascade may be controlled by a sort of negative feedback, in which the non-phosphorylated merlin exerts a suppression of cdc42 and rac1, thus promoting myelination. The SC transition toward the bipolar morphology, thus, initiates the myelination process (panel B). In mature SCs, the neuroactive steroid ALLO, via a GABA-A dependent mechanism, can modulate Src and FAK. This activation promotes the myelination, thus representing a potential approach towards the regulation of SC maturation, likely in post-injury conditions (panel C). ALLO: Allopregnanolone; cdc42: cell division control protein 42; FAK: focal adhesion kinase; GABA-A: γ-aminobutyric acid-A; rac1: Ras-related C3 botulinum toxin substrate.

Figure 3

Scheme of Hippo/YAP involvement in SCs. Hippo/YAP participates in forming tight-junction, thus regulating cell adhesion properties of SCs. However, in normal cells YAP localizes mainly in the nucleus, where it controls proliferation and apoptosis. A physical/mechanical injury or an environmental challenge, such as the exposure to a 50 Hz electromagnetic field, may induce a merlin-dependent Hippo/YAP activation; this process affects SC proliferation, migration and differentiation. YAP increases in the cytoplasm, losing its tumor suppressor activity, likely inducing the onco-transformation of SCs and the schwannoma development. SCs: Schwann cells; YAP: Yes-associated protein.