A Circadian Output in Drosophila Mediated by Neurofibromatosis-1 and Ras/MAPK

Abstract

Output from the circadian clock controls rhythmic behavior through poorly understood mechanisms. In Drosophila , null mutations of the neurofibromatosis-1 ( Nf1 ) gene produce abnormalities of circadian rhythms in locomotor activity. Mutant flies show normal oscillations of the clock genes period ( per ) and timeless ( tim ) and of their corresponding proteins, but altered oscillations and levels of a clock-controlled reporter. Mitogen-activated protein kinase (MAPK) activity is increased in Nf1 mutants, and the circadian phenotype is rescued by loss-of-function mutations in the Ras/MAPK pathway. Thus, 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 from clock cells, suggesting a coupling of PDF to Ras/MAPK signaling.