Early Days of Tenascin-R Research: Two Approaches Discovered and Shed Light on Tenascin-R

THE PATH TO TENASCIN-RIt has taken nearly 30 years.But finally, studies on cohorts of patients seem to be shedding some light on a protein that has been surfaced from time to time in the neurobiological literature.Tenascin-R, as it is now known, has proven a slippery quarry.That almost works as a pun, given the fact that in certain contexts, the molecule interferes with cell adhesion.The protein was first identified in chicken and rodents in the late 1980s among a large number of molecules associated with axons.Significant efforts were being made to untangle the mysteries of axon growth, fasciculation and pathfinding (1).Monoclonal antibody approaches turned up a number of immunoglobulin (Ig)-like cell adhesion proteins (2) which, introduced into cell cultures, influenced the development of neurites (3).One of these was an IgCAM that interacted with the plasma membrane via covalently linked glycosylphosphatidylinositol; it was variously termed F11 protein, F3 or contactinnowadays contactin1 (4-9).Immunoaffinity isolates of contactin1 yielded a complex of at least two polypeptides.The major component was contactin1, at 130 kDa, and along with it a minor partner at about 170 kDa.Further biochemical and immunological experiments showed that the minor component was unrelated to the 130 kDa contactin1, suggesting they had copurified (5, 10).Antibodies to the 170 kDa protein revealed that it was expressed in the developing nervous system, in a pattern partly overlapping with that of contactin1 but spatially much more restricted.In the spinal cord, for example, it was found on the ventral side around motor neurons during embryonic development.This position suggested a name: restrictin (11).Independently, the same protein was discovered in the Schachner laboratory through different means: using the L2 monoclonal antibody directed to the L2/HNK-1 carbohydrate moiety (12), which captured several glycosylated proteins from neural tissues.These included, IgCAMs, tenascin-C (initially named J1-200/220) and tenascin-R (christened J1-160/180 or janusin by Schachner and her colleagues) (13). STRUCTURAL FEATURES AND THE TENASCIN FAMILYThe experiments in chick and rodents had turned up homologs, as became clear through molecular cloning and sequencing of the chick and rat cDNAs.This showed that the components of restrictin and J1-160/180 represented the products of a common gene, and proteins were based on a set of structural motifs found in tenascin-C (14-18).These include an N-terminal cysteine-rich segment with three heptad repeats, followed by 4.5 EGF-like domains, nine fibronectin type III domains, and a C-terminal knob.