Autonomous and non-autonomous regulation of mammalian neurite development by Notch1 and Delta1

Background: On the basis of experiments suggesting that Notch and Delta hav e a role in axonal development in Drosophila neurons, we studied the abilit y of components of the Notch signaling pathway to modulate neurite formatio n in mammalian neuroblastoma cells in vitro. Results: We observed that N2a neuroblastoma cells expressing an activated f orm of Notch, Notch1(IC), produced shorter neurites compared with controls, whereas N2a cell lines expressing a dominant-negative Notch1 or a dominant -negative Delta1 construct extended longer neurites with a greater number o f primary neurites. We then compared the effects on neurites of contacting Delta1 on another cell and of overexpression of Delta1 in the neurite-exten ding cell itself. We found that N2a cells co-cultured with Delta1-expressin g quail cells produced fewer and shorter neuritic processes. On the other h and, high levels of Delta1 expressed in the N2a cells themselves stimulated neurite extension, increased numbers of primary neurites and induced expre ssion of Jagged1 and Notch1. Conclusions: These studies show that Notch signals can antagonize neurite o utgrowth and that repressing endogenous Notch signals enhances neurite outg rowth in neuroblastoma cells. Notch signals therefore act as regulators of neuritic extension in neuroblastoma cells. The response of neuritic process es to Delta1 expressed in the neurite was opposite to that to Delta1 contac ted on another cell, however. These results suggest a model in which develo ping neurons determine their extent of process outgrowth on the basis of th e opposing influences on Notch signals of ligands contacted on another cell and ligands expressed in the same cell. (C) 1999 Elsevier Science Ltd. Aii rights reserved.