Baylor College of Medicine Researchers Identify “Booster Stations” Along Central Nervous System Channels
Researchers at Houston’s Baylor College of Medicine have determined that as electrical signals travel from neuron to neuron along central nervous system axons, they are regenerated by “booster stations” called nodes of Ranvier, analogically to how phone, data, or video signals are maintained along networks by line signal amplifiers that boost reception quality. Without these nodes functioning efficiently, electrical communication breaks down in the nervous system, and the Baylor College research team reports that they have uncovered the necessary components that make up and assemble those booster sites.
In a report in the current edition of the journal Neuron (Neuron, Volume 78, Issue 3, 469-482, 8 May 2013) , Dr. Matthew N. Rasband, professor of neuroscience at Baylor College of Medicine, and colleagues describe how they’ve identified three partially redundant mechanisms that work together to build nodes of Ranvier, all dependent on the crucial myelin sheath that surrounds the axon that is necessary for proper central nervous system function.
The article is entitled “Three Mechanisms Assemble Central Nervous System Nodes of Ranvier,” by corresponding author Dr. Rasband along with co-authors: assistant professor of neuroscience at BCM Dr. Keiichiro Susuki; graduate student in the BCM developmental biology program Kae-Jiun Chang; BCM graduate student in neuroscience Daniel R. Zollinger; BCM research technician in neuroscience Yanhong Liu, assistant professor with Meiji Pharmaceutical University, Tokyo, Yasuhiro Ogawa, Yael Eshed-Eisenbach and Elior Peles, both with the Weizmann Institute of Science, Israel; Maria T. Dours-Zimmerman and Dieter R. Zimmermann, both with the University Hospital Zürich, Switzerland; Juan A. Oses-Prieto and Alma L. Burlingame of the University of California at San Francisco; Constanze I. Seidenbecherof Leibniz Institute for Neurobiology at at Magdeberg, Germany; and and Toshitaka Oohashi, Okayama University Graduate School of Medicine. Toshitaka Oohashi of Japan’s Okayama University Graduate School of Medicine.
We show that if you eliminate one of the mechanisms, the other two compensate and nodes of Ranvier still form. However, if two are eliminated, the booster stations fail to assemble,” says Dr. Rasband in a Baylor release. “It is remarkable, but makes sense, that multiple ‘back-up’ mechanisms exist to build a structure as important to the functioning of the nervous system as the nodes of Ranvier”
Dr. Rasband, along with coauthors Baylor’s Dr. Keiichiro Susuki and Kae-Jiun Chang and their colleagues, used a genetic strategy to demonstrate the existence and overlapping functions of the three mechanisms. Their study required a detailed analysis of 13 different knockout mouse models to show what happens when each piece is missing.
Highlights of the Neuron report include:
• A complex extracellular matrix (ECM) surrounds CNS nodes and binds to NF186
• Mutant mice lacking two mechanisms have impaired Na+ channel clustering
• ECM, paranodal, and cytoskeletal mechanisms assemble CNS nodes
The report’s abstract notes that rapid action potential propagation in myelinated axons requires Na+ channel clustering at nodes of Ranvier, but the mechanism of clustering at CNS nodes remains poorly understood. In their findings the authors we show that the assembly of nodes of Ranvier in the CNS involves three mechanisms: 1) a glia-derived extracellular matrix (ECM) complex containing proteoglycans; 2) adhesion molecules that cluster NF186, paranodal axoglial junctions that function as barriers to restrict the position of nodal proteins; and 3) axonal cytoskeletal scaffolds (CSs) that stabilize nodal Na+ channels. The researchers show that while mice with a single disrupted mechanism had mostly normal nodes, disruptions of the ECM and paranodal barrier, the ECM and CS, or the paranodal barrier and CS — all lead to juvenile lethality, profound motor dysfunction, and significantly reduced Na+ channel clustering. Our results demonstrate that ECM, paranodal, and axonal cytoskeletal mechanisms ensure robust CNS nodal Na+ channel clustering.
“The first mechanism contributing to node assembly is a glia-derived extracellular matrix complex. This complex binds to and stabilizes axonal receptors along axons so they can function as an attachment site for the proteins and ion channels needed for the formation of the node.
“The second mechanism is also glia-dependent. As the myelin sheaths mature, axon-glia junctions form between the myelin sheath and axon. As the myelin sheath extends along the axon and gets longer, the axon-glia junctions function almost like snowplows, forcing the molecules associated with the nodes of Ranvier toward each other, allowing them to cluster within the gap between the adjacent myelin sheaths.
“The third component, made up of axonal cytoskeletal scaffolds, acts as an anchor, securing the entire complex in place.”
“All of these processes depend on interaction with the myelinating glial cell,” explains Dr. Rasband. “There are some disorders, like multiple sclerosis and spinal cord injury, where the overlying myelin sheath is lost, and you lose the ability to maintain the nodes of Ranvier. You effectively lose the booster stations and the electrical signal dies out before reaching its destination. Therefore, any therapeutic strategy aimed at nervous system repair or regeneration must consider how nodes are built.”
He adds that the identification of the extracellular matrix complex as an organizing mechanism also has implications for spinal cord injury, since many of these same extracellular matrix molecules inhibit spinal cord regeneration. Some newer spinal cord injury treatments destroy this extracellular matrix complex so regrowth and repair might occur.
“This leads us to ask, ‘would this treatment have the negative side effect that inhibits reassembly of nodes of Ranvier?’ Our results show that the multiple overlapping mechanisms of node assembly can compensate for the loss of the extracellular matrix. Our study reveals how nodes in the central nervous system form, moving us that much closer to more effective therapeutic options,” Rasband observes. “Our team’s findings have far reaching implications for a variety of neurological disorders.”
Dr. Rasband, whose particular scientific interest is the role of neuronal-glial signaling in brain development, function, injury and disease, notes that his long range research goals are to elucidate the processes that underlie the molecular assembly of electrogenic compartments of axons and the role that myelinating cells (oligodendrocytes and Schwann cells) play in this process in health and in disease.
“Our lab explores the molecular basis of signaling between glial cells and axons in the brain and spinal cord under a variety of conditions including the normal process of myelination that occurs during development, demyelination and remyelination in disorders such as multiple sclerosis and the responses of axons and their myelinating cells to injuries of various types, including trauma. Our laboratory is working to understand the underlying mechanisms that regulate the clustering of ion channels at the sites that initiate and propagate action potentials: the axon initial segment and nodes of Ranvier.
“Many nervous system diseases and injuries result in the disruption of these domains. For example, traumatic brain and spinal cord injury (TBI and SCI), as well as demyelinating diseases like multiple sclerosis result in widespread axonal injury. It is now appreciated that a host of molecular events occurs that ultimately results in the disruption of axons and their excitable domains. One particularly sensitive component of axons is the spectrin/ankyrin based cytoskeleton. Spectrins and ankyrins are highly enriched at axon initial segments and nodes of Ranvier and are essential for maintaining both the high-density cluster of ion channels. Our research team is working to uncover the molecular mechanisms regulating formation and maintenance of ion channel clusters in axons since any therapeutic strategy aimed at nervous system repair and/or regeneration will require the re-establishment of these excitable domains.”
Funding for the study published in Neuron was from the National Institutes of Health grants NS069688, NS044916 and NS50220; the Dr. Miriam and Sheldon Adelson Medical Research Foundation; the Ministry of Education, Culture, Sports Science, and Technology of Japan 24107516; and the U.S. – Israel Binational Science Foundation.