Ion channel clustering in myelinated axons is essential for proper nervous system function. Ion channels are clustered at nodes of Ranvier through neuron-glia interactions. However, the mechanisms responsible for channel clustering remain poorly understood. Recent studies suggest that multiple mechanisms may contribute to node formation. Among these, the axonal submembranous cytoskeleton comprised of ankyrins and spectrins has been proposed to be key components. In particular, nodes of Ranvier themselves are enriched with ankyrinG (ankG) and ?IV spectrin;ankG is thought to bind directly to the Na+ and K+ channels, and then link to the actin cytoskeleton through ?IV spectrin. At paranodes, both ankyrinB and ?II spectrin are clustered, although their functions at paranodes remain unknown. Paranodes are also thought to function as a paranodal diffusion barrier and a second mechanism to mediate ion channel clustering at nodes, although the mechanisms responsible for this barrier function remain unknown. Furthermore, a major impediment to elucidating the function of paranodes is the relatively few proteins that have been identified at this site. In this proposal we will seek to determine the function of the nodal and paranodal cytoskeletons in node of Ranvier assembly and maintenance. We will do this using three new mouse models that utilize Cre-Lox technology to control the temporal and spatial (cell-type specific) expression of ankG, ankB, and ?II spectrin. We will silence expression of these proteins in peripheral sensory neurons, in retinal ganglion cells, and in myelinating glia during both development and in adults. Finally, we will use proteomic methods to identify new paranodal proteins, and then seek to determine their functions.

Public Health Relevance

Nodes of Ranvier are required for proper nervous system function, and many diseases or injuries disrupt nodes. Therapies for nervous system diseases will require a detailed understanding of how nodes form. We propose that the cytoskeleton consisting of ankyrins and spectrins plays important roles in node assembly and maintenance. We have developed a variety of mutant mouse models that will allow us to test this idea.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37NS044916-14
Application #
8687750
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Jakeman, Lyn B
Project Start
2002-09-30
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
14
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77030
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Huang, Yu-Mei; Rasband, Matthew N (2016) Organization of the axon initial segment: Actin like a fence. J Cell Biol 215:9-11
Ko, Kwang Woo; Rasband, Matthew N; Meseguer, Victor et al. (2016) Serotonin modulates spike probability in the axon initial segment through HCN channels. Nat Neurosci 19:826-34
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
Lee, Hyun Kyoung; Chaboub, Lesley S; Zhu, Wenyi et al. (2015) Daam2-PIP5K is a regulatory pathway for Wnt signaling and therapeutic target for remyelination in the CNS. Neuron 85:1227-43
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
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

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