A circadian output in Drosophila mediated by neurofibromatosis-1 and Ras/MAPK.
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.
Williams
J A
JA
Howard Hughes Medical Institute, Center for Sleep and Respiratory Neurobiology, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Su
H S
HS
Bernards
A
A
Field
J
J
Sehgal
A
A
D000483:Alleles; D000818:Animals; D001683:Biological Clocks; D001921:Brain / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D002940:Circadian Rhythm; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004330:Drosophila / Q000235:genetics / Q000502:physiology*; D029721:Drosophila Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D017344:Genes, Insect; D016514:Genes, Neurofibromatosis 1; D019476:Insect Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008297:Male; D009043:Motor Activity; D009154:Mutation; D009411:Nerve Endings / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D056950:Period Circadian Proteins; D010766:Phosphorylation; D015398:Signal Transduction; D019076:Transgenes; D020703:ras GTPase-Activating Proteins; D018631:ras Proteins / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D029721:Drosophila Proteins; D019476:Insect Proteins; C105590:NF1 protein, Drosophila; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; C539040:PER protein, Drosophila; D056950:Period Circadian Proteins; C113883:pdf protein, Drosophila; D020703:ras GTPase-Activating Proteins; C096445:tim protein, Drosophila; D017868:Cyclic AMP-Dependent Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; C086795:rl protein, Drosophila; D018631:ras Proteins