title: The Polarity Protein Pals1 Regulates Radial Sorting of Axons.
abstract: Myelin is essential for rapid and efficient action potential propagation in vertebrates. However, the molecular mechanisms regulating myelination remain incompletely characterized. For example, even before myelination begins in the PNS, Schwann cells must radially sort axons to form 1:1 associations. Schwann cells then ensheathe and wrap axons, and establish polarized, subcellular domains, including apical and basolateral domains, paranodes, and Schmidt-Lanterman incisures. Intriguingly, polarity proteins, such as Pals1/Mpp5, are highly enriched in some of these domains, suggesting that they may regulate the polarity of Schwann cells and myelination. To test this, we generated mice with Schwann cells and oligodendrocytes that lack Pals1. During early development of the PNS, Pals1-deficient mice had impaired radial sorting of axons, delayed myelination, and reduced nerve conduction velocities. Although myelination and conduction velocities eventually recovered, polyaxonal myelination remained a prominent feature of adult Pals1-deficient nerves. Despite the enrichment of Pals1 at paranodes and incisures of control mice, nodes of Ranvier and paranodes were unaffected in Pals1-deficient mice, although we measured a significant increase in the number of incisures. As in other polarized cells, we found that Pals1 interacts with Par3 and loss of Pals1 reduced levels of Par3 in Schwann cells. In the CNS, loss of Pals1 affected neither myelination nor the establishment of polarized membrane domains. These results demonstrate that Schwann cells and oligodendrocytes use distinct mechanisms to control their polarity, and that radial sorting in the PNS is a key polarization event that requires Pals1. Significance statement: This paper reveals the role of the canonical polarity protein Pals1 in radial sorting of axons by Schwann cells. Radial sorting is essential for efficient and proper myelination and is disrupted in some types of congenital muscular dystrophy.
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, and.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Zollinger
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, and.
authors.forename: Kae-Jiun
authors.initials: KJ
authors.lastname: Chang
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, and.
authors.forename: Kelli
authors.initials: K
authors.lastname: Baalman
authors.affiliation: Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140.
authors.forename: Seonhee
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, and rasband@bcm.edu.
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Rasband
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D016764:Cell Polarity / Q000502:physiology*; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D046529:Microscopy, Electron, Transmission; D009186:Myelin Sheath / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology*; D009703:Nucleoside-Phosphate Kinase / Q000378:metabolism*; D009836:Oligodendroglia / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012583:Schwann Cells / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D009703:Nucleoside-Phosphate Kinase; C499979:Mpp5 protein, mouse
keywords: Schwann cell; axon; myelin; polarity