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© The Rockefeller University Press, 0021-9525/1997//1495 $5.00
The Journal of Cell Biology, Volume 139, Number 6, , 1997 1495-1506

Article

The Axonal Membrane Protein Caspr, a Homologue of Neurexin IV, Is a Component of the Septate-like Paranodal Junctions That Assemble during Myelination



Steven Einheber*, George Zanazzi*, William Ching*, Steven Scherer||, Teresa A. Milner, Elior Peles**, and James L. Salzer*,{ddagger},§

* Department of Cell Biology, {ddagger} Department of Neurology, § The Kaplan Cancer Center, New York University Medical School, New York 10016; || Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; Department of Neurology and Neuroscience, Division of Neurobiology, Cornell University Medical College, New York 10021; and ** Sugen, Inc., Redwood City, California 94063

We have investigated the potential role of contactin and contactin-associated protein (Caspr) in the axonal–glial interactions of myelination. In the nervous system, contactin is expressed by neurons, oligodendrocytes, and their progenitors, but not by Schwann cells. Expression of Caspr, a homologue of Neurexin IV, is restricted to neurons. Both contactin and Caspr are uniformly expressed at high levels on the surface of unensheathed neurites and are downregulated during myelination in vitro and in vivo. Contactin is downregulated along the entire myelinated nerve fiber. In contrast, Caspr expression initially remains elevated along segments of neurites associated with nascent myelin sheaths. With further maturation, Caspr is downregulated in the internode and becomes strikingly concentrated in the paranodal regions of the axon, suggesting that it redistributes from the internode to these sites. Caspr expression is similarly restricted to the paranodes of mature myelinated axons in the peripheral and central nervous systems; it is more diffusely and persistently expressed in gray matter and on unmyelinated axons. Immunoelectron microscopy demonstrated that Caspr is localized to the septate-like junctions that form between axons and the paranodal loops of myelinating cells. Caspr is poorly extracted by nonionic detergents, suggesting that it is associated with the axon cytoskeleton at these junctions. These results indicate that contactin and Caspr function independently during myelination and that their expression is regulated by glial ensheathment. They strongly implicate Caspr as a major transmembrane component of the paranodal junctions, whose molecular composition has previously been unknown, and suggest its role in the reciprocal signaling between axons and glia.

Abbreviations used in this paper: CAM, cell adhesion molecule; Caspr, contactin-associated protein; CNS and PNS, central and peripheral nervous system; dPBS, Dulbecco's PBS; DRG, dorsal root ganglia; MAG, myelin-associated glycoprotein; MBP, myelin basic protein.

Address all correspondence to Dr. James L. Salzer, Department of Cell Biology, New York University Medical School, 550 First Avenue, New York, NY 10016. Tel.: (212) 263-5358. Fax: (212) 263-8139.

Elior Peles' current address is Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.


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