Disruption of sphingolipid metabolism elicits apoptosis-associated reproductive defects in Drosophila.

Sphingolipid signaling is thought to regulate apoptosis via mechanisms that are dependent on the concentration of ceramide relative to that of sphingosine-1-phosphate (S1P). This study reports defects in reproductive structures and function that are associated with enhanced apoptosis in Drosophila Sply05091 mutants that lack functional S1P lyase and thereby accumulate sphingolipid long chain base metabolites. Analyses of reproductive structures in these adult mutants unmasked multiple abnormalities, including supernumerary spermathecae, degenerative ovaries, and severely reduced testes. TUNEL assessment revealed increased cell death in mutant egg chambers at most oogenic stages and in affected mutant testes. These reproductive abnormalities and elevated gonadal apoptosis were also observed, to varying degrees, in other mutants affecting sphingolipid metabolism. Importantly, the reproductive defects seen in the Sply05091 mutants were ameliorated both by a second site mutation in the lace gene that restores long chain base levels towards normal and by genetic disruption of the proapoptotic genes reaper, hid and grim. These data thus provide the first evidence in Drosophila that accumulated sphingolipids trigger elevated levels of apoptosis via the modulation of known signaling pathways.