In a report in the current edition of Neuron, Dr. Matthew Rasband, professor of neuroscience at Baylor College of Medicine, and colleagues identified three partially redundant mechanisms that work together to build nodes of Ranvier, all dependent on the myelin sheath that surrounds the axon that is necessary for proper central nervous system function.
“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,” said Rasband, corresponding author on the study. “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”
Rasband, along with coauthors Dr. Keiichiro Susuki, assistant professor of neuroscience at BCM, and Kae-Jiun Chang, a graduate student in the developmental biology program at BCM, 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.
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,” said 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.”
Rasband 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 said. “Our team’s findings have far reaching implications for a variety of neurological disorders.”
Others who took part in this study include Daniel Zollinger, graduate student in neuroscience at BCM; Yanhong Liu, research technician in neuroscience at BCM; Yasuhiro Ogawa, formerly with BCM and currently an assistant professor with Meiji Pharmaceutical University, Tokyo; 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, both with the University of California San Francisco; Constanze I. Seidenbecher, Leibniz Institute for Neurobiology; and Toshitaka Oohashi, Okayama University Graduate School of Medicine.
Funding for this research 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.
Graciela Gutierrez713-798-4710 firstname.lastname@example.org