Internodal specializations of myelinated axons in the central nervous system

149

169

Paranodal junctions of myelinated nerve fibers are important for saltatory conduction and function as paracellular and membrane protein diffusion barriers flanking nodes of Ranvier. The formation of these specialized axoglial contacts depends on the presence of three cell adhesion molecules: neurofascin 155 on the glial membrane and a complex of Caspr and contactin on the axon. We isolated axonal and glial membranes highly enriched in these paranodal proteins and then used mass spectrometry to identify additional proteins associated with the paranodal axoglial junction. This strategy led to the identification of three novel components of the paranodal cytoskeleton: ankyrinB, ␣II spectrin, and ␤II spectrin. Biochemical and immunohistochemical analyses revealed that these proteins associate with protein 4.1B in a macromolecular complex that is concentrated at central and peripheral paranodal junctions in the adult and during early myelination. Furthermore, we show that the paranodal localization of ankyrinB is disrupted in Caspr-null mice with aberrant paranodal junctions, demonstrating that paranodal neuron-glia interactions regulate the organization of the underlying cytoskeleton. In contrast, genetic disruption of the juxtaparanodal protein Caspr2 or the nodal cytoskeletal protein ␤IV spectrin did not alter the paranodal cytoskeleton. Our results demonstrate that the paranodal junction contains specialized cytoskeletal components that may be important to stabilize axon-glia interactions and contribute to the membrane protein diffusion barrier found at paranodes.

Section: The Paranodal Cytoskeleton Remains Intact After Myelin Retramentioning

confidence: 57%

Spectrins and AnkyrinB Constitute a Specialized Paranodal Cytoskeleton

Ogawa¹,

Schafer²,

Horresh³

et al. 2006

149

169

“…3B). Nodal KCNQ3 staining was not apparent in gray matter, which contains an even higher density of nodes (Arroyo et al, 2001). Both the smaller sizes of nodes and the higher level of KCNQ3 staining in gray matter may contribute to the difficulty in detecting KCNQ3-positive nodes.…”

Section: Distribution Of Kcnq3 In Spinal Cordmentioning

confidence: 98%

KCNQ2 Is a Nodal K⁺Channel

Devaux¹,

Kleopa²,

Cooper³

et al. 2004

426

367

Mutations in the gene encoding the K ϩ channel KCNQ2 cause neonatal epilepsy and myokymia, indicating that KCNQ2 regulates the excitability of CNS neurons and motor axons, respectively. We show here that KCNQ2 channels are functional components of axon initial segments and nodes of Ranvier, colocalizing with ankyrin-G and voltage-dependent Na ϩ channels throughout the CNS and PNS. Retigabine, which opens KCNQ channels, diminishes axonal excitability. Linopirdine, which blocks KCNQ channels, prolongs the repolarization of the action potential in neonatal nerves. The clustering of KCNQ2 at nodes and initial segments lags that of ankyrin-G during development, and both ankyrin-G and KCNQ2 can be coimmunoprecipitated in the brain. KCNQ3 is also a component of some initial segments and nodes in the brain. The diminished activity of mutant KCNQ2 channels accounts for neonatal epilepsy and myokymia; the cellular locus of these effects may be axonal initial segments and nodes.

“…From an electrophysiological standpoint, the most important aspect of this interaction is the assembly and maintenance of heterotypic, adhesive junctions between axons and myelin sheaths (Koles and Rasminsky, 1972). These axoglial junctions, composed of neuronal and oligodendroglial components, serve several essential functions: they flank and define nodes of Ranvier, they impede the movement of interstitial ions and other molecules into the periaxonal space, and they compartmentalize the axolemma into at least three distinct subdomains: nodes of Ranvier, paranodes, and juxtaparanodes (for review, see Arroyo et al, 2001;Bhat, 2003;Salzer, 2003).…”

Section: Introductionmentioning

confidence: 99%

CNS Myelin Paranodes Require Nkx6-2 Homeoprotein Transcriptional Activity for Normal Structure

Southwood

Garbern

et al. 2004

Homeodomain proteins play critical roles during development in cell fate determination and proliferation, but few studies have defined gene regulatory networks for this class of transcription factors in differentiated cells. Using a lacZ-knock-in strategy to ablate Nkx6-2, we find that the Nkx6-2 promoter is active embryonically in neuroblasts and postnatally in oligodendrocytes. In addition to neurological deficits, we find widespread ultrastructural abnormalities in CNS white matter and aberrant expression of three genes encoding a paranodal microtubule destabilizing protein, stathmin 1, and the paranodal cell adhesion molecules neurofascin and contactin. The involvement of these downstream proteins in cytoskeletal function and cell adhesion reveals mechanisms whereby Nkx6-2 directly or indirectly regulates axon-glial interactions at myelin paranodes. Nkx6-2 does not appear to be the central regulator of axoglial junction assembly; nonetheless, our data constitute the first evidence of such a regulatory network and provide novel insights into the mechanism and effector molecules that are involved.