Expression of drop-dead (drd) in the tracheae is sufficient to prevent neurodegeneration, but not early lethality. Christine L. Sansone, Edward M. Blumenthal. Biological Sci, Marquette Univ, Milwaukee, WI.

   Mutation of the adult lethal gene drop-dead (drd) causes a number of phenotypes in addition to short lifespan, including neurodegeneration, fragile tracheae, reduced movement of food through the gut and subsequent starvation, small body size, and female sterility. The drd gene product is an integral membrane protein with limited homology to prokaryotic acyltransferases, but its biochemical function remains unknown. In this study, we have used tissue-specific knockdown and rescue of drd expression in order to determine the cause of the neurodegeneration phenotype. Knockdown of drd in glia (repo-Gal4 or 17A-Gal4), neurons (elav-Gal4) or both cell types did not cause adult lethality. In contrast, knockdown of drd in the tracheae (btl-Gal4) caused early adult lethality and neurodegeneration. The gut phenotypes of starvation and reduced food movement were not affected by knockdown of drd expression in the tracheae. Surprisingly, rescue of drd expression in the tracheae rescued neurodegeneration, but not adult lethality or gut dysfunction. From these data, we conclude that adult lethality in drd mutant flies has two independent causes: a tracheal defect that results in neurodegeneration and a gut defect that results in starvation. Either of these appears sufficient to cause early lethality. The fragile tracheae phenotype observed in drd mutants is predicted to cause hypoxia-induced neurodegeneration. To test this model directly, we crossed the hypoxia-sensitive LDH-Gal4 and LDH-LacZ reporters onto a drd mutant background. Expression of these transgenes was not elevated in drd mutants, suggesting that these flies are not hypoxic. Therefore, our data suggest that the absence of drd expression in the tracheae causes neurodegeneration by a mechanism other than hypoxia. Supported by Marquette University, a U.S. Department of Education GAANN fellowship to C.L.S. and NIH 1R15 GM080682-01 to E.M.B.