A dimeric version of the short N-cadherin binding motif HAVDI promotes neuronal cell survival by activating an N-cadherin/fibroblast growth factor receptor signalling cascade.

Abstract The HAVDI and INPISGQ sequences have been identified as functional binding motifs in extracellular domain 1 (ECD1) of N-cadherin. Cyclic peptides containing a tandem repeat of the individual motifs function as N-cadherin agonists and stimulate neurite outgrowth. We now show that the cyclic peptide N -Ac- CHAVDINGHAVDIC -NH 2 (SW4) containing the HAVDI sequence in tandem is efficacious also in promoting the in vitro survival of several populations of central nervous system neurons in paradigms where fibroblast growth factor-2 (FGF-2) is active. SW4 supported the survival of rat postnatal cerebellar granule neurons plated in serum-free medium and limited the death of differentiated granule neurons induced to die by switch to low K + medium. In addition, SW4 rescued embryonic hippocampal and cortical neurons from injury caused by glutamic acid excitotoxicity. The neuroprotective effects of SW4 displayed a concentration dependence similar to those inducing neuritogenesis, were inhibited by a monomeric version of the same motif and by a specific FGF receptor antagonist (PD173074), and were not mimicked by the linear peptide. Inhibitors of the phosphatidylinositol 3-kinase (PI 3-kinase), MAP kinase, and p38 kinase signalling pathways did not interfere with SW4 function. These data suggest that SW4 functions by binding to and clustering N-cadherin in neurons and thereby activating and N-cadherin/FGF receptor signalling cascade, and propose that such agonists may represent a starting point for the development of therapeutic agents promoting neuronal cell survival and regeneration.