βII-spectrin promotes mouse brain connectivity through stabilizing axonal plasma membranes and enabling axonal organelle transport

beta II-spectrin is the generally expressed member of the beta-spectrin family of elongated polypeptides that form micrometer-scale networks associated with plasma membranes. We addressed in vivo functions of beta II-spectrin in neurons by knockout of beta II-spectrin in mouse neural progenitors. beta II-spectrin deficiency caused severe defects in long-range axonal connectivity and axonal degeneration. beta II-spectrin-null neurons exhibited reduced axon growth, loss of actin-spectrin-based periodic membrane skeleton, and impaired bidirectional axonal transport of synaptic cargo. We found that beta II-spectrin associates with KIF3A, KIF5B, KIF1A, and dynactin, implicating spectrin in the coupling of motors and synaptic cargo. beta II-spectrin required phosphoinositide lipid binding to promote axonal transport and restore axon growth. Knockout of ankyrin-B (AnkB), a beta II-spectrin partner, primarily impaired retrograde organelle transport, while double knockout of beta II-spectrin and AnkB nearly eliminated transport. Thus, beta II-spectrin promotes both axon growth and axon stability through establishing the actin-spectrin-based membrane-associated periodic skeleton as well as enabling axonal transport of synaptic cargo.