Contactin orchestrates assembly of the septate-like junctions at the paranode in myelinated peripheral nerve

Rapid nerve impulse conduction depends on specialized membrane domains in m yelinated nerve, the node of Ranvier, the paranode, and the myelinated inte rnodal region. We report that GPI-linked contactin enables the formation of the paranodal septate-like axo-glial junctions in myelinated peripheral ne rve. Contactin clusters at the paranodal axolemma during Schwann cell myeli nation. Ablation of contactin in mutant mice disrupts junctional attachment at the paranode and reduces nerve conduction velocity 3-fold. The mutation impedes intracellular transport and surface expression of Caspr and leaves NF155 on apposing paranodal myelin disengaged. The contactin mutation does not affect sodium channel clustering at the nodes of Ranvier but alters th e location of the Shaker-type Kv1.1 and Kv1.2 potassium channels. Thus, con tactin is a crucial part in the machinery that controls junctional attachme nt at the paranode and ultimately the physiology of myelinated nerve.