Tenascin-R (TN-R), an extracellular matrix glycoprotein of the CNS, localizes to nodes of Ranvier and perineuronal nets and interacts in vitro with other extracellular matrix components and recognition molecules of the immunoglobulin superfamily. To characterize the functional roles of TN-R in vivo, we have generated mice deficient for TN-R by homologous recombination using embryonic stem cells. TN-R-deficient mice are viable and fertile. The anatomy of all major brain areas and the formation

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... d structure of myelin appear normal. However, immunostaining for the chondroitin sulfate proteoglycan phosphacan, a high-affinity ligand for TN-R, is weak and diffuse in the mutant when compared with wild-type mice. Compound action potential recordings from optic nerves of mutant mice show a significant decrease in conduction velocity as compared with controls. However, at nodes of Ranvier there is no apparent change in expression and distribution of Na ϩ channels, which are thought to bind to TN-R via their ␤2 subunit. The distribution of carbohydrate epitopes of perineuronal nets recognized by the lectin Wisteria floribunda or antibodies to the HNK-1 carbohydrate on somata and dendrites of cortical and hippocampal interneurons is abnormal. These observations indicate an essential role for TN-R in the formation of perineuronal nets and in normal conduction velocity of optic nerve. The extracellular matrix (EC M) is a complex network of macromolecules that includes glycoproteins, polysaccharides, and proteoglycans. These provide mechanical strength, scaffolding, and support to tissues and organs, and they participate in cellular differentiation. In the nervous system, interactions of neuronal and glial cells with the EC M regulate cell migration, survival, and differentiation, axonal pathfinding, and synapse formation. The tenascin family constitutes a group of extracellular matrix proteins displaying a common structure (for review, see Chiquet-Ehrismann et al., 1994; Erickson, 1994) . At the amino terminus, a signal sequence is followed by a cysteine-rich stretch, epidermal growth factor-like (EGF) repeats, fibronectin-type III (FN) homologous repeats, and a fibrinogen-like (FG) domain at the C terminus. The number of EGF domains is characteristic for each member of the family, whereas because of alternative splicing, the number of FN repeats may vary, and isoforms of tenascin (TN)-C and TN-R exist, differing in the number of FN repeats. Currently, five members of the tenascin family (TN-C, TN-R, TN-X, TN-Y, TN-W) have been identified in diverse species from zebrafish to humans (for review, see Bristow et al.