βIV-spectrin forms a diffusion barrier against L1CAM at the axon initial segment

Axonal and somatodendritic plasma membranes of polarized neurons express distinct sets of functional molecules. It is known that the neuronal polarity can be maintained by a barrier that impedes diffusional mixing of membrane components between the two domains. Using βIV-spectrin knockout mice, we demonstrate the involvement of this cytoskeletal protein in the formation of a barrier that selectively blocks lateral mobility of L1 cell adhesion molecule (L1CAM) at the axon initial segment of hippocampal neurons. We also show that the βIV-spectrin-based barrier is required for the axon-specific distribution of L1CAM both in vitro and in vivo. The barrier activity against L1CAM may depend on direct interactions of L1CAM with ankyrin_G, a protein binding to βIV-spectrin, rather than on steric hindrance by other transmembrane proteins clustered at the axon initial segment. Our results highlight the role of βIV-spectrin and ankyrin_G as critical components of a selective barrier against L1CAM.