THE CHEMOREPULSIVE ACTIVITY OF SECRETED SEMAPHORINS IS REGULATED BY FURIN-DEPENDENT PROTEOLYTIC PROCESSING

The semaphorins are a large group of cell surface and secreted protein s implicated in axonal pathfinding. Here we show that the secreted mou se semaphorin D (SemD) is synthesized as an inactive precursor (proSem D) and becomes repulsive for sensory and sympathetic neurites upon pro teolytic cleavage, ProSemD processing can be blocked completely by an inhibitor selective for furin-like endoproteases or mutagenesis of thr ee conserved dibasic cleavage sites. Its C-terminal pro-peptide contai ns a processing signal that is essential for SemD to acquire its full repulsive activity. SemD processing is regulated during the embryonic development of the mouse and determines the magnitude of its repulsive activity. Similarly to SemD, the secreted semaphorins SemA and SemE d isplay repulsive properties that are regulated by processing, Our data suggest that differential proteolytic processing determines the repul sive potency of secreted semaphorins and implicate proteolysis as an i mportant regulatory mechanism in axonal pathfinding.