Tenascin-C promotes neurite outgrowth of embryonic hippocampal neurons through the alternatively spliced fibronectin type III BD domains via activation of the cell adhesion molecule F3/contactin.

Tenascin-C is a multimodular glycoprotein that possesses neurite outgrowth-stimulating properties, and one functional site has been localized to the alternatively spliced fibronectin type III domain D. To identify the neuronal receptor that mediates this effect, neighboring pairs of fibronectin type III domains were expressed as hybrid proteins fused to the Fc fragment of human immunoglobulin. These IgFc fusions were tested for neurite outgrowth-promoting properties on embryonic day 18 rat hippocampal neurons, and both the combinations BD and D6 were shown to promote the elongation of the longest process, the prospective axon. Antibodies to the cell adhesion molecule F3/contactin of the Ig superfamily blocked the BD- but not the D6-dependent effect. Biochemical studies using F3/contactin-IgFc chimeric proteins confirmed that the adhesion molecule selectively reacts with the combination BD but not with other pairs of fibronectin type III repeats of tenascin-C. The alternatively spliced BD cassettes are prominently expressed in the developing hippocampus, as shown by reverse transcription PCR, and colocalize with F3 expression during perinatal periods when axon growth and the establishment of hippocampal connections take place. We conclude that F3/contactin regulates axon growth of hippocampal neurons in response to tenascin-C.