DEVELOPMENTAL EXPRESSION OF THE PROHORMONE CONVERTASES PC1 AND PC2 IN MOUSE PANCREATIC-ISLETS

The immunocytochemical distribution and messenger RNA expression of the prohormone convertases PC1 and PC2 involved in the posttranslational processing of precursor proteins were analyzed in mouse and rat pancreatic islets. Immunocytochemical colocalization studies demonstrated a close association of insulin with both PC1 and PC2 in the adult mouse and rat pancreas. The coexpression of insulin with the prohormone convertases was further examined in rat pancreatic tumors induced by streptozotocin-nicotinamide treatment. These insulin-synthesizing tumors expressed PC1 and PC2, whereas insulin-silent adenomas did not. Colocalization studies demonstrated that only PC2, not PC1, colocalizes with glucagon, pancreatic polypeptide, and somatostatin. The highest levels of PC2-like immunoreactivity were observed in the glucagon-containing alpha-cells. Ontogeny studies carried out by in situ hybridization in mice showed the first detectable expression of the prohormone convertases in the pancreatic primordium at midgestation, starting for PC1 on embryonic day 11 and for PC2 on embryonic day 10. Enzyme expression was further confirmed by immunocytochemistry, which detected the presence of immunoreactive PC1- and PC2-like proteins on embryonic days 14 and 17, respectively. Taken together, our data suggest that both PC1 and PC2 play a role in proinsulin processing in vivo, whereas PC2 is a likely candidate convertase participating in the processing of proglucagon, propancreatic polypeptide, and prosomatostatin in pancreatic islets.