Rapid and efficient propagation of action potentials in the mammalian nervous system requires both myelination and the high-density clustering of voltage-gated ion channels at gaps in the myelin sheath called nodes of Ranvier. Although many demyelinating diseases and injuries cause disruption of nodes and nervous system dysfunction, the mechanisms that are responsible for ion channel clustering at central nervous system (CNS) nodes of Ranvier remain unknown. We propose that three distinct cellular and molecular interactions contribute to CNS node formation and maintenance: 1) interactions between axonal cell adhesion molecules and a unique CNS nodal extracellular matrix, 2) interactions between axons and myelinating glia at paranodal junctions set up a membrane protein diffusion barrier to restrict the lateral mobility of nodal proteins, and 3) interactions between nodal membrane proteins and nodal cytoskeletal scaffolds maintain high density clusters of ion channels. Thus, multiple, overlapping mechanisms may exist in the CNS to facilitate ion channel clustering at nodes of Ranvier. In this project we will undertake both cell biological and genetic methods to determine the mechanisms underlying CNS node of Ranvier formation. We will focus on the extrinsic, glial-derived interactions that are necessary for CNS node formation. In the first aim we will elucidate the molecular interactions between nodal cell adhesion molecules and CNS nodal ECM proteins. We will determine if soluble ECM proteins are sufficient to induce clustering of nodal proteins in purified neuronal cultures. In the second aim we will perform genetic analyses of single, double, and triple knockout mice lacking extracellular matrix molecules, paranodal junctions, and/or cytoskeletal interactions to uncover the existence of, and requirement for, each overlapping mechanism.

Public Health Relevance

Disruption of nodes of Ranvier or their molecular composition is one consequence of demyelination and contributes to the pathophysiology of many diseases and injuries including multiple sclerosis and spinal cord injury. Thus, any therapeutic effort aimed at treating these diseases or reversing their devastating effects will require a detailed understanding of the mechanisms responsible for node of Ranvier formation and maintenance. Nodes have been the focus of much interest not only because of their functional importance in both health and disease, but also because their assembly represents one of the best examples of the elaborate reciprocal interactions that must occur between neurons and glial cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS069688-04
Application #
8448711
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Jakeman, Lyn B
Project Start
2010-05-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$323,755
Indirect Cost
$116,883
Name
Baylor College of Medicine
Department
Neurosciences
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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
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
Rasband, Matthew N (2016) Glial Contributions to Neural Function and Disease. Mol Cell Proteomics 15:355-61
Marin, Miguel A; Ziburkus, Jokubus; Jankowsky, Joanna et al. (2016) Amyloid-β plaques disrupt axon initial segments. Exp Neurol 281:93-8
Zollinger, Daniel R; Chang, Kae-Jiun; Baalman, Kelli et al. (2015) The Polarity Protein Pals1 Regulates Radial Sorting of Axons. J Neurosci 35:10474-84
Hirono, Moritoshi; Ogawa, Yasuhiro; Misono, Kaori et al. (2015) BK Channels Localize to the Paranodal Junction and Regulate Action Potentials in Myelinated Axons of Cerebellar Purkinje Cells. J Neurosci 35:7082-94
Baalman, Kelli; Marin, Miguel A; Ho, Tammy Szu-Yu et al. (2015) Axon initial segment-associated microglia. J Neurosci 35:2283-92
Normand, Elizabeth A; Rasband, Matthew N (2015) Subcellular patterning: axonal domains with specialized structure and function. Dev Cell 32:459-68
Rasband, Matthew N; Peles, Elior (2015) The Nodes of Ranvier: Molecular Assembly and Maintenance. Cold Spring Harb Perspect Biol 8:a020495

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