Glial βii spectrin contributes to paranode formation and maintenance

Action potential conduction along myelinated axons depends on high densities of voltage-gated Na channels at the nodes of Ranvier. Flanking each node, paranodal junctions (paranodes) are formed between axons and Schwann cells in the peripheral nervous system (PNS) or oligodendrocytes intheCNS. Paranodal junctions contribute to both no deassembly and maintenance. Despitetheir importance, the molecular mechanisms responsible for paranode assembly and maintenance remain poorly understood. βII spectrin is expressed in diverse cells and is an essential part of the submembranous cytoskeleton. Here, we show that Schwann cell βII spectrin is highly enriched at paranodes. To elucidate the roles of glial βII spectrin, we generated mutant mice lacking βII spectrin in myelinating glial cells by crossing mice with a floxed allele of Sptbn1 with Cnp-Cre mice, and analyzed both male and female mice. Juvenile (4 weeks) and middle-aged (60 weeks) mutant mice showed reduced grip strength and sciatic nerve conduction slowing, whereas no phenotype was observed between 8 and 24 weeks of age. Consistent with these findings, immunofluorescence microscopy revealed disorganized paranodes in the PNS and CNS of both postnatal day 13 and middle-aged mutant mice, but not in young adult mutant mice. Electron microscopy confirmed partial loss of transverse bands at the paranodal axoglial junction in the middle-aged mutant mice in both the PNS and CNS. These findings demonstrate that a spectrin-based cytoskeleton in myelinating glia contributes to formation and maintenance of paranodal junctions.Fil: Susuki, Keiichiro. Baylor College of Medicine; Estados UnidosFil: Zollinger, Daniel R.. Baylor College of Medicine; Estados UnidosFil: Chang, Kae Jiun. Baylor College of Medicine; Estados UnidosFil: Zhang, Chuansheng. Baylor College of Medicine; Estados UnidosFil: Huang, Claire Yu Mei. Baylor College of Medicine; Estados UnidosFil: Tsai, Chang Ru. Baylor College of Medicine; Estados UnidosFil: Galiano, Mauricio Raul. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina. Baylor College of Medicine; Estados UnidosFil: Liu, Yanhong. Baylor College of Medicine; Estados UnidosFil: Benusa, Savannah D.. Virginia Commonwealth University; Estados UnidosFil: Yermakov, Leonid M.. Wright State University; Estados UnidosFil: Griggs, Ryan B.. Wright State University; Estados UnidosFil: Dupree, Jeffrey L.. Virginia Commonwealth University; Estados UnidosFil: Rasband, Matthew N.. Baylor College of Medicine; Estados Unido

Glial ankyrins facilitate paranodal axoglial junction assembly

Neuron-glia interactions establish functional membrane domains along myelinated axons. These include nodes of Ranvier, paranodal axoglial junctions, and juxtaparanodes. Paranodal junctions are the largest vertebrate junctional adhesion complex, are essential for rapid saltatory conduction, and contribute to assembly and maintenance of nodes. However, the molecular mechanisms underlying paranodal junction assembly are poorly understood. Ankyrins are cytoskeletal scaffolds traditionally associated with Na+ channel clustering in neurons and important for membrane domain establishment and maintenance in many cell types. Here, we show that ankyrinB, expressed by Schwann cells, and ankyrinG, expressed by oligodendrocytes, are highly enriched at the glial side of paranodal junctions where they interact with the essential glial junctional component neurofascin 155. Conditional knockout of ankyrins in oligodendrocytes disrupts paranodal junction assembly and delays nerve conduction during early development in mice. Thus, glial ankyrins function as major scaffolds that facilitate early and efficient paranodal junction assembly in the developing central nervous system

Remodeling myelination: implications for mechanisms of neural plasticity

One of the most significant paradigm shifts in membrane remodeling is the emerging view that membrane transformation is not exclusively controlled by cytoskeletal rearrangement, but also by biophysical constraints, adhesive forces, membrane curvature and compaction. One of the most exquisite examples of membrane remodeling is myelination. The advent of myelin was instrumental in advancing the nervous system during vertebrate evolution. With more rapid and efficient communication between neurons, faster and more complex computations could be performed in a given time and space. Our knowledge of how myelin-forming oligodendrocytes select and wrap axons has been limited by insufficient spatial and temporal resolution. By virtue of recent technological advances, progress has clarified longstanding controversies in the field. Here we review insights into myelination, from target selection to axon wrapping and membrane compaction, and discuss how understanding these processes has unexpectedly opened new avenues of insight into myelination-centered mechanisms of neural plasticity

Timing measurement unit with multi-stage TVC for embedded memories

[[abstract]]To fmd the maximum access time for embedded memories, a wide range and scalable time-to-digital converter (TDC) composed of multi-stage time-to-voltage converter (TVC), peak voltage detector, voltage-to-time converter (VTC) and ring counter is present. Four-stage TVC is applied in the TDC to measure the time intervals of 311.5 to 16Ons and 5OOps resolution with external clock 50MHz. After calibration, the measured maximum error and linearity error are one LSB and 0.62590, respectively.[[fileno]]2030110030010[[department]]電機工程學

TDP-43 maximizes nerve conduction velocity by repressing a cryptic exon for paranodal junction assembly in Schwann cells

10.7554/elife.64456eLife10e6445

Three mechanisms assemble central nervous system nodes of ranvier

Rapid action potential propagation in myelinated axons requires Na(+) channel clustering at nodes of Ranvier. However, the mechanism of clustering at CNS nodes remains poorly understood. Here, we show that the assembly of nodes of Ranvier in the CNS involves three mechanisms: a glia-derived extracellular matrix (ECM) complex containing proteoglycans and adhesion molecules that cluster NF186, paranodal axoglial junctions that function as barriers to restrict the position of nodal proteins, and axonal cytoskeletal scaffolds (CSs) that stabilize nodal Na(+) channels. We 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