James Salzer1, M. Laura Feltri2,3,4 and Claire Jacob5 1Neuroscience Institute, New York University Grossman School of Medicine, New York, New York 10016, USA 2Institute for Myelin and Glia Exploration, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York 14203, USA 3IRCCS Neurological Institute Carlo Besta, Milano 20133, Italy 4Department of Biotechnology and Translational Sciences, Universita’ Degli Studi di Milano, Milano 20133, Italy 5Faculty of Biology, Institute of Developmental Biology and Neurobiology, Johannes Gutenberg University Mainz, Mainz 55128, Germany Correspondence: James.Salzernyulangone.org

Glial cells in the peripheral nervous system (PNS), which arise from the neural crest, include axon-associated Schwann cells (SCs) in nerves, synapse-associated SCs at the neuromuscular junction, enteric glia, perikaryon-associated satellite cells in ganglia, and boundary cap cells at the border between the central nervous system (CNS) and the PNS. Here, we focus on axon-associated SCs. These SCs progress through a series of formative stages, which culminate in the generation of myelinating SCs that wrap large-caliber axons and of nonmyelinating (Remak) SCs that enclose multiple, small-caliber axons. In this work, we describe SC development, extrinsic signals from the axon and extracellular matrix (ECM) and the intracellular signaling pathways they activate that regulate SC development, and the morphogenesis and organization of myelinating SCs and the myelin sheath. We review the impact of SCs on the biology and integrity of axons and their emerging role in regulating peripheral nerve architecture. Finally, we explain how transcription and epigenetic factors control and fine-tune SC development and myelination.