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 and neuron-glia interactions remain poorly understood. Our work shows that multiple glia-dependent mechanisms contribute to node formation. Furthermore, these mechanisms converge on axonal and glial ankyrin and spectrin cytoskeletons. In this project, we will determine the importance of nodal spectrin cytoskeletons by analyzing conditional knockout mice lacking ?I and ?IV spectrins, singly and in combination. We also discovered that AnkyrinR (AnkR) can function as secondary Na+ channel clustering mechanism. However, the primary functions of AnkR in the nervous system are unknown. We generated a conditional allele for AnkR and will use this in loss-of-function studies to determine the role of AnkR in various cells throughout the nervous system. We performed differential proteomics on WT and AnkR-deficient brains together with immunoprecipitation to identify AnkR interacting proteins. We will investigate these interactions to further define the functions of AnkR in the nervous system. Finally, in a discovery aim, we will use a newly generated mouse (Nfasc-BioID) to perform in vivo proximity biotinylation at nodes and paranodes. We will then capture these proteins using streptavidin affinity purification, followed by mass spectrometry to identify biotinylated proteins. This will begin to uncover the node and paranode interactomes. We will validate and investigate these biotinylated proteins through localization, and gain and loss of function studies both in vitro and in vivo.

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 the mechanisms of node assembly and maintenance. We will determine the role of the axonal cytoskeleton in these mechanisms and identify new proteins associated with nodes and paranodes.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Synapses, Cytoskeleton and Trafficking Study Section (SYN)
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Jakeman, Lyn B
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Baylor College of Medicine
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United States
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Huang, Claire Yu-Mei; Rasband, Matthew N (2018) Axon initial segments: structure, function, and disease. Ann N Y Acad Sci 1420:46-61
Susuki, Keiichiro; Zollinger, Daniel R; Chang, Kae-Jiun et al. (2018) Glial ?II Spectrin Contributes to Paranode Formation and Maintenance. J Neurosci 38:6063-6075
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
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
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
Huang, Yu-Mei; Rasband, Matthew N (2016) Organization of the axon initial segment: Actin like a fence. J Cell Biol 215:9-11

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