Developmental Changes in Expression of βIV Spectrin Splice Variants at Axon Inital Segments and Nodes of Ranvier

Axon initial segments (AIS) and nodes of Ranvier are highly specialized axonal membrane domains enriched in Na+ channels. These Na+ channel clusters play essential roles in action potential initiation and propagation. AIS and nodal Na+ channel complexes are linked to the actin cytoskeleton through beta IV spectrin. However, neuronal beta IV spectrin exists as two main splice variants: a longer beta IV Sigma 1 variant with canonical N-terminal actin and aII spectrin-binding domains, and a shorter beta IV Sigma 6 variant lacking these domains. Here, we show that the predominant neuronal beta IV spectrin splice variant detected in the developing brain switches from beta IV Sigma 1 to beta IV Sigma 6, and that this switch is correlated with expression changes in ankyrinG (ankG) splice variants. We show that beta IV Sigma 1 is the predominant splice variant at nascent and developing AIS and nodes of Ranvier, but with increasing age and in adults beta IV Sigma 6 becomes the main splice variant. Remarkably, super-resolution microscopy revealed that the spacing of spectrin tetramers between actin rings remains unchanged, but that shorter spectrin tetramers may also be present. Thus, during development beta IV spectrin may undergo a switch in the splice variants found at AIS and nodes of Ranvier.