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Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.

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Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition.

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Cell Adhesion Molecules in Myelination

and .

Correspondence to David R. Colman, Brookdale Center for Molecular Biology, Box 1126, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029.

Myelin is formed by the compaction of oligodendrocyte plasma membranes in the CNS or Schwann cell plasma membranes in the PNS as the plasma membrane spirals around the axon. For myelin to function efficiently, a tight apposition of these membranes must be maintained, which, when viewed by electron microscopy, displays a uniform and reproducible spacing between the layers (see Chap. 4). Given the close association of myelin membranes, it is not surprising that CAMs play major roles in the formation and maintenance of this plasma membrane organelle. There is strong evidence supporting a role for CAMs in the initiation of myelination, in the compaction of myelin membranes and in the stability of the noncompacted as well as the compact layers of myelin, the axon-myelin interface and the nodes of Ranvier.

The myelinating cell, when brought into contact with a large axon, begins to synthesize vast amounts of plasma membrane. The molecular trigger that starts this process is not yet known, but the interaction of MAG with some axonal component has been suggested to play an important role. The next steps in myelin formation are membrane synthesis, axonal wrapping and compaction. While MAG in both the CNS and PNS is located at the axon-myelin interface and is therefore likely to play a role in membrane spiraling, different molecules are responsible for membrane compaction in the two systems. In PNS myelin, the most abundant protein is P0, a small protein containing a single extracellular Ig domain [31] (see Chap. 4). The P0 protein is responsible for adhesion at the apposition of extracellular surfaces, or intraperiod line, via homophilic interactions of its Ig domain, and at the major dense line, where cytoplasmic surfaces come together via interactions of the highly negatively charged cytoplasmic domain of P0 with the acidic lipids, mostly phosphatidylserine, of the opposing membrane. Therefore, P0 protein can be regarded as a “bifunctional” adhesion molecule. It is interesting that P0 is an “obligatory” adhesion molecule in that it induces strong cell—cell adhesion between any cells in which it is expressed [3234].

In the CNS of mammals, two proteins are needed to accomplish the dual role of adhesion at both myelin bilayer surfaces that P0 effects in the PNS. The four-transmembrane-domain proteolipid protein (PLP) is likely to be responsible for adhesion of the extracellular surfaces, while the very basic cytoplasmic myelin basic protein (MBP) holds membranes together at the inner cytoplasmic surfaces in the CNS. Although MBP is also present in the PNS, it is much less abundant than in the CNS and its absence does not have a dramatic effect on PNS myelin compaction.

The importance of P0 in PNS myelin has been clearly demonstrated. In P0 gene knockout experiments in mice [35], severe hypomyelination and a virtual absence of compact myelin in the PNS is observed. In humans, there are two disease states associated with mutations in the P0 gene: Charcot-Marie-Tooth type I disease (see Chaps. 39 and 40) and Dejerine-Sottas disease, both dysmyelinating diseases that exhibit a spectrum of severity depending on the particular mutation.

The crystal structure of the extracellular domain of P0 has also been determined [36]. The arrangement of molecules in the crystal indicates that P0 may exist on the membrane surface as a tetramer (Fig. 7-8) that can link to other tetramers from the opposing membrane to form an adhesive lattice, like a “molecular Velcro.” The structure also suggests that P0 mediates adhesion through the direct interaction of apically directed tryptophan side chains with the opposing membrane [37], in addition to homophilic protein—protein interaction.

Figure 7-8. Structure of the P0 protomer.

Figure 7-8

Structure of the P0 protomer. A: In this ribbon diagram of the extracellular domain of P0, each β strand is labeled with a letter and two antiparallel β sheets are formed. The disulfide bridge is indicated in dark orange and a hypothetical (more...)

Functional myelin not only depends on compact myelin in the internodes but also requires maintenance of a stable structure in the membranes adjacent to the nodes of Ranvier, termed the paranodes, which are sinuous, open cytoplasmic channels that are continuous with each other throughout the myelin sheath. In the plasma membrane subdomains that surround these channels, a number of adhesion molecules have been localized, namely, MAG, certain integrins [38] and cadherins. The paranodal loops interact across their extracellular surfaces, and it is clear that certain cadherins at least participate in holding them firmly in place against each other [39]. In particular, E-cadherin is expressed by Schwann cells and is localized to these cytoplasmic compartments. This cadherin is not present in the underlying axon. Thus, in peripheral nerve, E-cadherin is unusual in that it does not mediate adhesion between two cells but, instead, mediates adhesion between two regions of a single plasma membrane elaborated by a single Schwann cell.

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 1999, American Society for Neurochemistry.
Bookshelf ID: NBK28158


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