p38 MAP kinase regulates circadian rhythms in Drosophila.
The large repertoire of circadian rhythms in diverse organisms depends on oscillating central clock genes, input pathways for entrainment, and output pathways for controlling rhythmic behaviors. Stress-activated p38 MAP Kinases (p38K), although sparsely investigated in this context, show circadian rhythmicity in mammalian brains and are considered part of the circadian output machinery in Neurospora. We find that Drosophila p38Kb is expressed in clock neurons, and mutants in p38Kb either are arrhythmic or have a longer free-running periodicity, especially as they age. Paradoxically, similar phenotypes are observed through either transgenic inhibition or activation of p38Kb in clock neurons, suggesting a requirement for optimal p38Kb function for normal free-running circadian rhythms. We also find that p38Kb genetically interacts with multiple downstream targets to regulate circadian locomotor rhythms. More specifically, p38Kb interacts with the period gene to regulate period length and the strength of rhythmicity. In addition, we show that p38Kb suppresses the arrhythmic behavior associated with inhibition of a second p38Kb target, the transcription factor Mef2. Finally, we find that manipulating p38K signaling in free-running conditions alters the expression of another downstream target, MNK/Lk6, which has been shown to cycle with the clock and to play a role in regulating circadian rhythms. These data suggest that p38Kb may affect circadian locomotor rhythms through the regulation of multiple downstream pathways.
Cell Biology Department, Emory University School of Medicine, Atlanta, Georgia Department of Biological Sciences, University of Denver, Denver, Colorado Alysia.Mortimer@du.edu.
Alysia D
AD
Vrailas-Mortimer
Department of Biological Sciences, University of Denver, Denver, Colorado.
Sarah M
SM
Ryan
Department of Biological Sciences, University of Denver, Denver, Colorado.
Matthew J
MJ
Avey
Department of Biological Sciences, University of Denver, Denver, Colorado.
Nathan T
NT
Mortimer
School of Biology and Ecology and Department of Mathematics and Statistics, University of Maine, Orono, Maine.
Harold
H
Dowse
Cell Biology Department, Emory University School of Medicine, Atlanta, Georgia Department of Neurology Research, BiogenIdec, Cambridge, Massachusetts.
Subhabrata
S
Sanyal
D000818:Animals; D030801:Animals, Genetically Modified; D057906:Circadian Clocks / Q000502:physiology; D002940:Circadian Rhythm / Q000502:physiology*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D020935:MAP Kinase Signaling System; D064326:MEF2 Transcription Factors / Q000502:physiology; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics; D050505:Mutant Proteins / Q000378:metabolism; D009474:Neurons / Q000201:enzymology*; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
D029721:Drosophila Proteins; D064326:MEF2 Transcription Factors; D050505:Mutant Proteins; C539040:PER protein, Drosophila; D056950:Period Circadian Proteins; D014157:Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases; C500415:Lk6 protein, Drosophila; D020929:Mitogen-Activated Protein Kinase Kinases
Drosophila; MNK/Lk6; Mef2; circadian rhythms; p38 MAP Kinase; period