Protein 4.1B Contributes to the Organization of Peripheral Myelinated Axons

Abstract

Neurons are characterized by extremely long axons. This exceptional cell shape is likely to depend on multiple factors including interactions between the cytoskeleton and membrane proteins. In many cell types, members of the protein 4.1 family play an important role in tethering the cortical actin-spectrin cytoskeleton to the plasma membrane. Protein 4.1B is localized in myelinated axons, enriched in paranodal and juxtaparanodal regions, and also all along the internodes, but not at nodes of Ranvier where are localized the voltage-dependent sodium channels responsible for action potential propagation. To shed light on the role of protein 4.1B in the general organization of myelinated peripheral axons, we studied 4.1B knockout mice. These mice displayed a mildly impaired gait and motility. Whereas nodes were unaffected, the distribution of Caspr/paranodin, which anchors 4.1B to the membrane, was disorganized in paranodal regions and its levels were decreased. In juxtaparanodes, the enrichment of Caspr2, which also interacts with 4.1B, and of the associated TAG-1 and Kv1.1, was absent in mutant mice, whereas their levels were unaltered. Ultrastructural abnormalities were observed both at paranodes and juxtaparanodes. Axon calibers were slightly diminished in phrenic nerves and preterminal motor axons were dysmorphic in skeletal muscle. βII spectrin enrichment was decreased along the axolemma. Electrophysiological recordings at 3 post-natal weeks showed the occurrence of spontaneous and evoked repetitive activity indicating neuronal hyperexcitability, without change in conduction velocity. Thus, our results show that in myelinated axons 4.1B contributes to the stabilization of membrane proteins at paranodes, to the clustering of juxtaparanodal proteins, and to the regulation of the internodal axon caliber.

The Kv1-associated molecules TAG-1 and Caspr2 are selectively targeted to the axon initial segment in hippocampal neurons

“…The role of Caspr2 and TAG-1 has been well established at the juxtaparanodes of myelinated axons where they mediate axo-glial contacts and induce the clustering of Kv1.1 and Kv1.2 to control the internodal resting potential (Poliak et al, 2003;Traka et al, 2003). The intracellular protein 4.1B (also known as EPB41L3), which binds Caspr2 is required for assembling the juxtaparanodal scaffold (Buttermore et al, 2011;Cifuentes-Diaz et al, 2011;Einheber et al, 2013;Horresh et al, 2010). In contrast to juxtaparanodes, Caspr2, and TAG-1, although present at the AIS are dispensable for the recruitment of Kv1 channels there (Duflocq et al, 2011;Inda et al, 2006;Ogawa et al, 2008).…”

Cadm3 (Necl-1) interferes with the activation of the PI3 kinase/Akt signaling cascade and inhibits Schwann cell myelinationin vitro

“…In that respect it is interesting to note the significant decrease in Cadm3 expression in the 4.1B knockout mouse (Einheber et al 2013) which exhibits an about 3-fold increase in the number of small caliber axons (1 μm) being myelinated in the sciatic nerve (Einheber et al 2013), as well as a slight, but significant, hyper-myelination across all axon diameters (Cifuentes-Diaz et al 2011; Einheber et al 2013). This is of course an indirect correlation, and it is quite possible that the phenotype observed in the 4.1B knockout mice is not related to the decrease in axon-derived Cadm3.…”

Systems Genetics Implicates Cytoskeletal Genes in Oocyte Control of Cloned Embryo Quality

“…Both Dlgap1 and Epb4.1l3 are components of the cortical cytoskeleton network and likely play roles in supporting cellular signaling. The Epb4.1 family comprises scaffolding proteins that interact with the ezrin-radixin-moesin complex and play a role in tethering the cortical actin-spectrin complex to the plasma membrane, regulating cell shape, intercellular junctions, ion balance, signaling, and control of cellular proliferation (Kuns et al 2005;Terada et al 2005;Cifuentes-Diaz et al 2011). Dlgap1 encodes a scaffold protein also known as GKAP/SAPAP1, which controls receptor functioning as well as microtubule dynamics and organization near the cell cortex and promotes centrosome positioning (Manneville et al 2010).…”