**4.1 Schwann cell differentiation and development**

During development, SCs surround bundles of axons and support them to outgrow by releasing growth factors such as nerve growth factor (NGF), glial cell linederived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), and neurotrophin (NT3) [12–14]. It follows a "radial sorting" of axons by extension of cellular process from Schwann cells, which begins to divide axon bundles into smaller ones and finally separate the neighboring axons with cell cytoplasm. Thus two types of fibers are formed: (i) unmyelinated Remak fibers, in which SC surrounds several small-sized axons (sensory and autonomic) and does not produce myelin, and (ii) myelinated fibers in which each large-sized axon is surrounded by a SC cell, 1:1 relationship, and a myelin sheath is formed by SC membrane spirally wrapping the axon [15]. Mesaxon is termed the point where the plasma membrane apposition is formed where the first encircling process meets itself. Remak SCs maintain the proliferative capacity of all the life [16].

During this stage, changes in cell morphology and gene expression occur, mediated by the transcription factor Krox-20 (or Egr-2) [17–19].

#### **4.2 Interactions between Schwann cells and axons**

The differentiation of Schwann cells is controlled by some **growth factors** among which the most important are in the neuregulin family. Neuregulins (Nrgs) are transmembrane proteins that signal through ErbB tyrosine kinase receptors [20]. Axonal neuregulin-1 (Nrg1), produced in many isoforms by alternative splicing (heregulin, glial growth factor, sensory and motor neuron-derived factor), interacts with ErbB2/ ErbB3 receptors tyrosine kinase expressed on Schwann cells [21–25]. ErbB2 and ErbB3 combine to act as heterodimers and efficiently bind Nrg1. **Nrg1/ErbB** signaling axis has a critical role in Schwann cell development (for review [26–28]) like survival, proliferation, migration, differentiation, and myelination [26, 29–32].

Nrgs need protease involvement for Nrg1-ErbB interactions because Nrgs are synthesized as single-pass transmembrane proteins and shed from the cell surface

#### *Schwann Cell Plasticity in Peripheral Nerve Regeneration after Injury DOI: http://dx.doi.org/10.5772/intechopen.91805*

by the proteolytic cleavage, thus permitting the interaction with ErbB receptors across the periaxonal space [33, 34].

Another enzyme implicated in Nrg1 cleavage is beta-amyloid converting enzyme (BACE1), a **beta-secretase** present in axon [35, 36]. An *in vivo* study showed that the BACE1-null mice presented reduced rates of Nrg1 cleavage and decreased PNS myelin, a low capacity of myelination with axons with a thinner myelin sheath [35].

An effect opposite to the BACE activity has tumor necrosis factor-alpha-converting enzyme (TACE), a neuronal alpha-secretase, cleaving Nrg1 into an inactive form [37]. TACE genetic inactivation in motor neurons caused hypermyelination like in Nrg1 overexpression.

Another factor that is essential in SCs-axon interaction, with a protection role for the axon, is **Schwann cell basal lamina**. The basal lamina together with extracellular collagen fibrils protects axons from extension and compression injuries. They provide good support for axonal outgrowth and guidance (reviewed by [38]). Basal lamina defines also Schwann cell orientation in axonal myelination [39]. More of this, SCs require axonal contact for secreting the components of basal lamina, so the relationship of axon-SCs via basal lamina is interactive and reciprocal [40, 41].

All these interactions described above are very important and may be modulated in the control of nerve regeneration.
