Ion channel clustering at nodes of Ranvier is an essential feature of myelinated axons. Nodal Na+ channel clusters confer several important functional advantages including decreased energy and space requirements, and increased action potential conduction velocity. We recently showed that multiple, overlapping mechanisms contribute to CNS node of Ranvier formation. These mechanisms include both intrinsic (neuronal) and extrinsic (glial mechanisms). Extrinsic mechanisms include interactions between axonal cell adhesion molecules and glia-derived extracellular matrix molecules, as well as an axoglial junction-dependent diffusion barrier that restricts membrane proteins to nodes. Intrinsic mechanisms depend on cytoskeletal and scaffolding proteins. The redundancy of nodal Na+ channel clustering mechanisms makes genetic mouse models the only tractable approach to discover how CNS nodes are formed. Despite these advances, the molecular details for how these mechanisms work remain poorly understood and are even controversial. Here, we will use newly developed genetic mouse models to elucidate the molecular mechanisms responsible for node of Ranvier formation and maintenance. We propose to determine the roles of NF186 and the nodal ECM in node of Ranvier assembly and maintenance. We propose to determine how spectrins function to link the nodal Na+ channel protein complex to the underlying actin cytoskeleton. And finally, we propose to determine how paranodes function as lateral diffusion barriers. The experiments proposed here continue and extend our previous studies that identified multiple, overlapping mechanisms for CNS node of Ranvier formation.
Nodes of Ranvier are essential for proper nervous system function. Here, we will elucidate the intrinsic (axonal) and extrinsic (glial) mechanisms that contribute to assembly of CNS nodes of Ranvier. We will use new genetic mouse models to uncover redundant mechanisms and pathways.
| Huang, Claire Yu-Mei; Rasband, Matthew N (2018) Axon initial segments: structure, function, and disease. Ann N Y Acad Sci 1420:46-61 |
| Wang, Chih-Chuan; Ortiz-González, Xilma R; Yum, Sabrina W et al. (2018) ?IV Spectrinopathies Cause Profound Intellectual Disability, Congenital Hypotonia, and Motor Axonal Neuropathy. Am J Hum Genet 102:1158-1168 |
| Huang, Claire Yu-Mei; Zhang, Chuansheng; Ho, Tammy Szu-Yu et al. (2017) ?II Spectrin Forms a Periodic Cytoskeleton at the Axon Initial Segment and Is Required for Nervous System Function. J Neurosci 37:11311-11322 |
| Marin, Miguel A; Rasband, Matthew N (2017) Reassembly of the axon initial segment and nodes of Ranvier in regenerated axons of the central nervous system. Neural Regen Res 12:1276-1277 |
| Amor, Veronique; Zhang, Chuansheng; Vainshtein, Anna et al. (2017) The paranodal cytoskeleton clusters Na+ channels at nodes of Ranvier. Elife 6: |
| Huang, Claire Yu-Mei; Zhang, Chuansheng; Zollinger, Daniel R et al. (2017) An ?II Spectrin-Based Cytoskeleton Protects Large-Diameter Myelinated Axons from Degeneration. J Neurosci 37:11323-11334 |
| Marin, Miguel A; Ziburkus, Jokubus; Jankowsky, Joanna et al. (2016) Amyloid-? plaques disrupt axon initial segments. Exp Neurol 281:93-8 |
| Zhang, Chuansheng; Rasband, Matthew N (2016) Cytoskeletal control of axon domain assembly and function. Curr Opin Neurobiol 39:116-21 |
| Huang, Yu-Mei; Rasband, Matthew N (2016) Organization of the axon initial segment: Actin like a fence. J Cell Biol 215:9-11 |
| Marin, Miguel A; de Lima, Silmara; Gilbert, Hui-Ya et al. (2016) Reassembly of Excitable Domains after CNS Axon Regeneration. J Neurosci 36:9148-60 |
Showing the most recent 10 out of 28 publications
