Physiological roles of axonal ankyrins in survival of premyelinated axons and localization of voltage-gated sodium channels

440 kD ankyrin-B and 480/270 kD ankyrin-G are membrane skeletal proteins wi th closely related biochemical properties yet distinctive physiological rol es in axons. These proteins associate with spectrin-actin networks and also bind to integral membrane proteins including the L1 CAM family of cell adh esion molecules and voltage-gated sodium channels. 440 kD ankyrin-B is expr essed with L1 in premyelinated axon tracts, and is essential for survival o f these axons, at least in the case of the optic nerve. 440 ankyrin-B may c ollaborate with L1 in transcellular structures that mediate axon fasciculat ion and mechanically stabilize axon bundles, although these proteins may al so be involved in axon pathfinding. Ankyrin-B (-/-) mice exhibit loss of L1 from premyelinated axon tracts and a similar, although much more severe, p henotype to L1 (-/-) mice and humans with L1 mutations. Ankyrin-B and L1 th us are candidates to collaborate in the same structural pathway and defects in this pathway can lead to nervous system malformations and mental retard ation. 480/270 kD ankyrin-G are highly concentrated along with the L1CAM fa mily members neurofascin and NrCAM at nodes of Ranvier and axon initial seg ments. Voltage-gated sodium channels bind directly to ankyrins, and are lik ely to associate in a ternary complex containing neurofascin/NrCAM, and ank yrin-G. Mice with ankyrin-G expression abolished in the cerebellum exhibit loss of ability of Purkinje neurons to fire action potentials, as well as l oss of restriction of neurofascin/NrCAM to axon initial segments. Ankyrin-G thus is a key component in assembly of functional components of the axon i nitial segment and possibly the node of Ranvier.