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

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Science  21 Sep 2001:
Vol. 293, Issue 5538, pp. 2251-2256
DOI: 10.1126/science.1063097

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Output from the circadian clock controls rhythmic behavior through poorly understood mechanisms. InDrosophila, null mutations of theneurofibromatosis-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 inDrosophila. 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.

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