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Science 293 (5538): 2251-2256

Copyright © 2001 by the American Association for the Advancement of Science

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

Julie A. Williams,12 Henry S. Su,12 Andre Bernards,4 Jeffrey Field,3 Amita Sehgal12*

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.

1 Howard Hughes Medical Institute,
2 Center for Sleep and Respiratory Neurobiology,
3 Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
4 Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
*   To whom correspondence should be addressed. E-mail: amita{at}mail.med.upenn.edu

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