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

• Published in: Science (American Association for the Advancement of Science) Vol. 293; no. 5538; pp. 2251 - 2256
• Main Authors: Williams, Julie A., Su, Henry S., Bernards, Andre, Field, Jeffrey, Sehgal, Amita
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for the Advancement of Science 21-09-2001; American Association for the Advancement of Science; The American Association for the Advancement of Science
• Subjects: Alleles; Analysis; Animals; Biochemistry; Biological and medical sciences; Biological Clocks; Brain - metabolism; Calcium-Calmodulin-Dependent Protein Kinases - genetics; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Circadian Rhythm; Circadian rhythms; Cyclic AMP Response Element-Binding Protein - genetics; Cyclic AMP Response Element-Binding Protein - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Drosophila; Drosophila - genetics; Drosophila - physiology; Drosophila Proteins; Enzymes; Extracellular Signal-Regulated MAP Kinases; Feedback (Response); Genes; Genes, Insect; Genes, Neurofibromatosis 1; Genetic mutation; Genotypes; Insect Proteins - genetics; Insect Proteins - metabolism; Insect Proteins - physiology; Insects; Locomotion; Male; MAP Kinase Signaling System; Medical sciences; Motor Activity; Mutation; Nerve Endings - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - physiology; Nerves; Neurofibroma; neurofibromatosis-1 (Nf1) gene; Neurological disorders; Neurology; Neurons; Neuropeptides - genetics; Neuropeptides - metabolism; Nf1 gene; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oscillation; period (per) gene; Period Circadian Proteins; period gene; Phenotypes; Phosphorylation; pigment-dispersing factor; Proteins; ras GTPase-Activating Proteins; ras Proteins - metabolism; Signal Transduction; timeless (tim) gene; timeless gene; Transgenes; Tumors of the nervous system. Phacomatoses; United States; Skin disease; Nervous system diseases; Phacomatosis; Insecta; Drosophila; Circadian rhythm; Experimental study; Genetic determinism; Neurofibromatosis Recklinghausen; Drosophilidae; Genetic disease; Arthropoda; Animal; Benign neoplasm; Behavior; Invertebrata; Diptera
• DOI: 10.1126/science.1063097
• EISSN: 1095-9203
• ISSN: 0036-8075

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.