A circadian output in Drosophila mediated by neurofibromatosis-1 and Ras/MAPK

Output from the circadian clock controls rhythmic behavior through poorly u nderstood mechanisms. In Drosophila, null mutations of the neurofibromatosi s-1 (Nf1) gene produce abnormalities of circadian rhythms in locomotor acti vity. Mutant flies show normal oscillations of the clock genes period (per) and timeless (tim) and of their corresponding proteins, but altered oscill ations and levels of a clock-controlled reporter. Mitogen-activated protein kinase (MAPK) activity is increased in Nf1 mutants, and the circadian phen otype is rescued by loss-of-function mutations in the Ras/MAPK pathway. Thu s, Nf1 signals through Ras/MAPK in Drosophila. Immunohistochemical staining revealed a circadian oscillation of phospho-MAPK in the vicinity of nerve terminals containing pigment-dispersing factor (PDF), a secreted output fro m clock cells, suggesting a coupling of PDF to Ras/MAPK signaling.