Reelin, the extracellular matrix protein deficient in reeler mutant mice, is processed by a metalloproteinase

Reelin is the extracellular protein defective in reeler mice. It is believe d that reelin acts via the extracellular matrix to influence the developmen t of nearby neurons, but the mechanism remains thus far unknown. In the pre sent work, we present in vivo and in vitro evidence that reelin is cleaved. This processing did not occur in Reln(rl-Orl) mutant mice in which reelin is not secreted and was prevented in explant cultures by brefeldin treatmen t, suggesting that it takes place extracellularly or in a postendoplasmic r eticulum compartment. Reelin cleavage was inhibited by zinc chelators known to inhibit metalloproteinases but was unaffected by inhibitors of serine, cysteine, or aspartate proteinases. Furthermore, reelin cleavage was insens itive to inhibitors of matrixins, neprilysin, meprin, and peptidyl dipeptid ase A suggesting that the processing enzyme belongs to a different enzyme f amily. This enzyme and the physiological meaning of reelin processing remai n to be characterized further. (C) 1999 Academic Press.