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Science 21 September 2001:
Vol. 293. no. 5538, pp. 2251 - 2256
DOI: 10.1126/science.1063097
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Reports

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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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
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J. Neurosci. 28, 4619-4623
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Circadian rhythmicity mediated by temporal regulation of the activity of p38 MAPK.
M. W. Vitalini, R. M. de Paula, C. S. Goldsmith, C. A. Jones, K. A. Borkovich, and D. Bell-Pedersen (2007)
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Circadian Transcription Depends on Limiting Amounts of the Transcription Co-activator nejire/CBP.
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Distinct Functional Domains of Neurofibromatosis Type 1 Regulate Immediate versus Long-Term Memory Formation.
I. S. Ho, F. Hannan, H.-F. Guo, I. Hakker, and Y. Zhong (2007)
J. Neurosci. 27, 6852-6857
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The band mutation in Neurospora crassa is a dominant allele of ras-1 implicating RAS signaling in circadian output.
W. J. Belden, L. F. Larrondo, A. C. Froehlich, M. Shi, C.-H. Chen, J. J. Loros, and J. C. Dunlap (2007)
Genes & Dev. 21, 1494-1505
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Mechanisms of Clock Output in the Drosophila Circadian Pacemaker System..
P. H. Taghert and O. T. Shafer (2006)
J Biol Rhythms 21, 445-457
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Reduced growth of Drosophila neurofibromatosis 1 mutants reflects a non-cell-autonomous requirement for GTPase-Activating Protein activity in larval neurons.
J. A. Walker, A. V. Tchoudakova, P. T. McKenney, S. Brill, D. Wu, G. S. Cowley, I. K. Hariharan, and A. Bernards (2006)
Genes & Dev. 20, 3311-3323
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The circadian clock modulates core steps in long-term memory formation in aplysia..
L. C. Lyons, M. S. Collado, O. Khabour, C. L. Green, and A. Eskin (2006)
J. Neurosci. 26, 8662-8671
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Effect of neurofibromatosis type I mutations on a novel pathway for adenylyl cyclase activation requiring neurofibromin and Ras.
F. Hannan, I. Ho, J. J. Tong, Y. Zhu, P. Nurnberg, and Y. Zhong (2006)
Hum. Mol. Genet. 15, 1087-1098
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Serine phosphorylation of mCRY1 and mCRY2 by mitogen-activated protein kinase.
K. Sanada, Y. Harada, M. Sakai, T. Todo, and Y. Fukada (2004)
Genes Cells 9, 697-708
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Circadian Regulation of cGMP-Gated Channels of Vertebrate Cone Photoreceptors: Role of cAMP and Ras.
G. Y.-P. Ko, M. L. Ko, and S. E. Dryer (2004)
J. Neurosci. 24, 1296-1304
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Drosophila doubletime Mutations Which either Shorten or Lengthen the Period of Circadian Rhythms Decrease the Protein Kinase Activity of Casein Kinase I.
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Temporal Regulation of Light-Induced Extracellular Signal-Regulated Kinase Activation in the Suprachiasmatic Nucleus.
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J Neurophysiol 90, 3854-3863
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Are Changes in MAPK/ERK Necessary or Sufficient for Entrainment in Chick Pineal Cells?.
G. Yadav, M. Straume, J. Heath III, and M. Zatz (2003)
J. Neurosci. 23, 10021-10031
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Genetic Models in Applied Physiology: Invited Review: Sleeping flies don't lie: the use of Drosophila melanogaster to study sleep and circadian rhythms.
J. C. Hendricks (2003)
J Appl Physiol 94, 1660-1672
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Neuronal Activity Is Required for the Circadian Rhythm of Vasopressin Gene Transcription in the Suprachiasmatic Nucleus in Vitro.
H. Arima, S. B. House, H. Gainer, and G. Aguilera (2002)
Endocrinology 143, 4165-4171
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The p42/44 Mitogen-activated Protein Kinase Pathway Couples Photic Input to Circadian Clock Entrainment.
G. Q. Butcher, H. Dziema, M. Collamore, P. W. Burgoon, and K. Obrietan (2002)
J. Biol. Chem. 277, 29519-29525
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Review Article : Neurofibromin in the Brain.
D. H. Gutmann (2002)
J Child Neurol 17, 592-601
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Review Article : Molecular and Cellular Mechanisms Underlying the Cognitive Deficits Associated With Neurofibromatosis 1.
R. M. Costa and A. J. Silva (2002)
J Child Neurol 17, 622-626
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Science. ISSN 0036-8075 (print), 1095-9203 (online)