nsf is essential for organization of myelinated axons in zebrafish.
BACKGROUND
Myelinated axons are essential for rapid conduction of action potentials in the vertebrate nervous system. Of particular importance are the nodes of Ranvier, sites of voltage-gated sodium channel clustering that allow action potentials to be propagated along myelinated axons by saltatory conduction. Despite their critical role in the function of myelinated axons, little is known about the mechanisms that organize the nodes of Ranvier.


RESULTS
Starting with a forward genetic screen in zebrafish, we have identified an essential requirement for nsf (N-ethylmaleimide sensitive factor) in the organization of myelinated axons. Previous work has shown that NSF is essential for membrane fusion in eukaryotes and has a critical role in vesicle fusion at chemical synapses. Zebrafish nsf mutants are paralyzed and have impaired response to light, reflecting disrupted nsf function in synaptic transmission and neural activity. In addition, nsf mutants exhibit defects in Myelin basic protein expression and in localization of sodium channel proteins at nodes of Ranvier. Analysis of chimeric larvae indicates that nsf functions autonomously in neurons, such that sodium channel clusters are evident in wild-type neurons transplanted into the nsf mutant hosts. Through pharmacological analyses, we show that neural activity and function of chemical synapses are not required for sodium channel clustering and myelination in the larval nervous system.


CONCLUSIONS
Zebrafish nsf mutants provide a novel vertebrate system to investigate Nsf function in vivo. Our results reveal a previously unknown role for nsf, independent of its function in synaptic vesicle fusion, in the formation of the nodes of Ranvier in the vertebrate nervous system.
Woods
Ian G
IG
Department of Developmental Biology, Stanford University, California 94305, USA.
Lyons
David A
DA
Voas
Matthew G
MG
Pogoda
Hans-Martin
HM
Talbot
William S
WS
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D016923:Cell Death / Q000502:physiology; D002678:Chimera / Q000378:metabolism; D005819:Genetic Markers; D006198:Hair Cells, Auditory / Q000502:physiology; D007814:Larva / Q000033:anatomy & histology / Q000235:genetics / Q000378:metabolism; D009068:Movement / Q000502:physiology; D009154:Mutation; D004676:Myelin Basic Protein / Q000235:genetics; D052066:N-Ethylmaleimide-Sensitive Proteins / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D011901:Ranvier's Nodes / Q000378:metabolism / Q000648:ultrastructure*; D015222:Sodium Channels / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000502:physiology*
D005819:Genetic Markers; D004676:Myelin Basic Protein; D012333:RNA, Messenger; D015222:Sodium Channels; D029961:Zebrafish Proteins; D052066:N-Ethylmaleimide-Sensitive Proteins; C511348:N-ethylmaleimide sensitive factor, zebrafish