title: The cytoskeletal adaptor protein band 4.1B is required for the maintenance of paranodal axoglial septate junctions in myelinated axons.
abstract: Precise targeting and maintenance of axonal domains in myelinated axons is essential for saltatory conduction. Caspr and Caspr2, which localize at paranodal and juxtaparanodal domains, contain binding sites for the cytoskeletal adaptor protein 4.1B. The exact role of 4.1B in the organization and maintenance of axonal domains is still not clear. Here, we report the generation and characterization of 4.1B-null mice. We show that loss of 4.1B in the PNS results in mislocalization of Caspr at paranodes and destabilization of paranodal axoglial septate junctions (AGSJs) as early as postnatal day 30. In the CNS, Caspr localization is progressively disrupted and ultrastructural analysis showed paranodal regions that were completely devoid of AGSJs, with axolemma separated from the myelin loops, and loops coming off the axolemma. Most importantly, our phenotypic analysis of previously generated 4.1B mutants, used in the study by Horresh et al. (2010), showed that Caspr localization was not affected in the PNS, even after 1 year; and 4.1R was neither expressed, nor enriched at the paranodes. Furthermore, ultrastructural analysis of these 4.1B mutants showed destabilization of CNS AGSJs at ∼ 1 year. We also discovered that the 4.1B locus is differentially expressed in the PNS and CNS, and generates multiple splice isoforms in the PNS, suggesting 4.1B may function differently in the PNS versus CNS. Together, our studies provide direct evidence that 4.1B plays a pivotal role in interactions between the paranodal AGSJs and axonal cytoskeleton, and that 4.1B is critically required for long-term maintenance of axonal domains in myelinated axons.
authors.affiliation: Department of Cell and Molecular Physiology, University of North Carolina Neuroscience Center, and Carolina Center for Developmental Disabilities, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA.
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Buttermore
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Dupree
authors.forename: JrGang
authors.initials: J
authors.lastname: Cheng
authors.forename: Xiuli
authors.initials: X
authors.lastname: An
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
authors.forename: Manzoor A
authors.initials: MA
authors.lastname: Bhat
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000648:ultrastructure; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism / Q000648:ultrastructure; D007365:Intercellular Junctions / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism*; D009413:Nerve Fibers, Myelinated / Q000378:metabolism* / Q000648:ultrastructure; D009431:Neural Conduction / Q000235:genetics / Q000502:physiology; D017933:Peripheral Nervous System / Q000378:metabolism / Q000648:ultrastructure; D051179:Plakins / Q000235:genetics* / Q000378:metabolism*; D011901:Ranvier's Nodes / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; C491322:Cntnap1 protein, mouse; C514956:Epb41 protein, mouse; C488402:Epb41l3 protein, mouse; D008840:Microfilament Proteins; D051179:Plakins