Whirlin, a cytoskeletal scaffolding protein, stabilizes the paranodal region and axonal cytoskeleton in myelinated axonsReport as inadecuate




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BMC Neuroscience

, 14:96

Cellular and molecular mechanisms

Abstract

BackgroundMyelinated axons are organized into distinct subcellular and molecular regions. Without proper organization, electrical nerve conduction is delayed, resulting in detrimental physiological outcomes. One such region is the paranode where axo-glial septate junctions act as a molecular fence to separate the sodium Na channel-enriched node from the potassium K channel-enriched juxtaparanode. A significant lack of knowledge remains as to cytoskeletal proteins which stabilize paranodal domains and underlying cytoskeleton. Whirlin Whrn is a PDZ domain-containing cytoskeletal scaffold whose absence in humans results in Usher Syndromes or variable deafness-blindness syndromes. Mutant Whirlin Whrn mouse model studies have linked such behavioral deficits to improper localization of critical transmembrane protein complexes in the ear and eye. Until now, no reports exist about the function of Whrn in myelinated axons.

ResultsRT-PCR and immunoblot analyses revealed expression of Whrn mRNA and Whrn full-length protein, respectively, in several stages of central and peripheral nervous system development. Comparing wild-type mice to Whrn knockout Whrn mice, we observed no significant differences in the expression of standard axonal domain markers by immunoblot analysis but observed and quantified a novel paranodal compaction phenotype in 4 to 8 week-old Whrn nerves. The paranodal compaction phenotype and associated cytoskeletal disruption was observed in Whrn mutant sciatic nerves and spinal cord fibers from early 2 week-old to late 1 year-old stages of development. Light and electron microscopic analyses of Whrn knockout mice reveal bead-like swellings in cerebellar Purkinje axons containing mitochondria and vesicles by both. These data suggest that Whrn plays a role in proper cytoskeletal organization in myelinated axons.

ConclusionsDomain organization in myelinated axons remains a complex developmental process. Here we demonstrate that loss of Whrn disrupts proper axonal domain organization. Whrn likely contributes to the stabilization of paranodal myelin loops and axonal cytoskeleton through yet unconfirmed cytoskeletal proteins. Paranodal abnormalities are consistently observed throughout development 2 wk-1 yr and similar between central and peripheral nervous systems. In conclusion, our observations suggest that Whrn is not required for the organization of axonal domains, but once organized, Whrn acts as a cytoskeletal linker to ensure proper paranodal compaction and stabilization of the axonal cytoskeleton in myelinated axons.

KeywordsMyelinated axons Axonal domains Paranodal domain Axonal cytoskeleton Whirlin AbbreviationsAGSJAxo-glial septate junction

WhrnWhirlin

CasprContactin-associated protein

4.1BProtein 4.1B brain band.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2202-14-96 contains supplementary material, which is available to authorized users.

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Author: James A Green - Jun Yang - M’hamed Grati - Bechara Kachar - Manzoor A Bhat

Source: https://link.springer.com/







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