Characterization of MEN1 in drosophila melanogaster

Abstract

Multiple endocrine neoplasia type 1 (MEN1) is a familial cancer syndrome characterized by a predisposition to tumors mostly in the parathyroid, pituitary, and endocrine pancreas. Tumorigenesis arises by somatic mutation in the MEN1 gene, but little is known about the relevance of menin to the MEN1 pathogenicity. Here, Drosophila MEN1 (Mnn1) models were developed to investigate the in vivo function of menin. Overexpression of Mnn1 in wing discs led to a thoracic microchaete-loss phenotype and dorsal region specific-overexpression to crumpled wings. Neither cell cycle arrest nor apoptosis were the cause for this crumpled-wing phenotype, but it turned out to be due to the defect in adhesions between the two wing blades during the process of adult wing expansion. In addition, the Mnn1 null mutants were generated for further study. They were viable and fertile, but their L5 wing veins were found truncated distal to the posterior crossvein. Unexpectedly, their insulin-producing cells, which are reported to be evolutionarily conserved with pancreatic beta-cells, did not increase in size nor did their amount of insulin compared to the wild type. Furthermore, it was demonstrated that the interaction between menin and JNK or TGF-ß pathway, which was reported previously with mammalian cells, could not be reproduced in Drosophila. Taken together, the two Mnn1 mutants, gain-of-function and loss-of-function mutants, revealed that Mnn1 might involve in the regulation of the wing, vein, and thoracic microchaete development through a novel pathway independent from JNK or TGF-ß pathways.