Abstract
Voltage-gated sodium channels cluster in macromolecular complexes at nodes of Ranvier to promote rapid nerve impulse conduction in vertebrate nerves. Node assembly in peripheral nerves is thought to be initiated at heminodes at the extremities of myelinating Schwann cells, and fusion of heminodes results in the establishment of nodes. Here we show that assembly of 'early clusters' of nodal proteins in the murine axonal membrane precedes heminode formation. The neurofascin (Nfasc) proteins are essential for node assembly, and the formation of early clusters also requires neuronal Nfasc. Early clusters are mobile and their proteins are dynamically recruited by lateral diffusion. They can undergo fusion not only with each other but also with heminodes, thus contributing to the development of nodes in peripheral axons. The formation of early clusters constitutes the earliest stage in peripheral node assembly and expands the repertoire of strategies that have evolved to establish these essential structures.
Highlights
Rapid propagation of action potentials in the myelinated nerve fibres of vertebrates requires the accumulation of macromolecular complexes containing voltage-gated sodium channels (Nav) at the nodes of Ranvier
Much has been learned about the composition and assembly of nodes, such as the role of proteins encoded by the neurofascin (Nfasc) gene, which is essential for node formation; how myelinating Schwann cells initiate the assembly of macromolecular axonal complexes containing Nav is still incompletely understood (Sherman et al, 2005; Zhang et al, 2012; Zhang et al, 2020; Eshed-Eisenbach et al, 2020; Rasband and Peles, 2021)
We examined the properties and fate of early clusters in dorsal root ganglia (DRG) neurons derived from transgenic mice co-cultured with WT rat Schwann cells
Summary
Rapid propagation of action potentials in the myelinated nerve fibres of vertebrates requires the accumulation of macromolecular complexes containing voltage-gated sodium channels (Nav) at the nodes of Ranvier. We show that ‘node-like clusters’ are the earliest detectable Nav-rich complexes of nodal proteins in primary sensory neurons, and their appearance requires the presence of myelinating Schwann cells Since their emergence anticipates that of heminodes, we describe them as early clusters. Clusters in PNS neurons in co-culture are mobile and highly dynamic and can disintegrate or fuse with each other The fact that their number peaks at early stages of myelination and gradually declines as the more stable heminodes appear suggested a developmental relationship between the two structures. We show that dynamic early clusters of nodal proteins in PNS nerves represent a Nfasc186dependent developmental stage of node assembly during myelination that precedes heminode formation These data underline the uniquely essential role of the Nfasc gene in node assembly in the PNS and the diverse strategies that have evolved to ensure the assembly of an essential domain in the vertebrate peripheral nervous system
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