title: An isoform-specific mutant reveals a role of PDP1 epsilon in the circadian oscillator.
abstract: The Drosophila PAR domain protein 1 (Pdp1) gene encodes a transcription factor with multiple functions. One isoform, PDP1epsilon, was proposed to be an essential activator of the core clock gene, Clock (Clk). However, a central clock function for PDP1epsilon was recently disputed, and genetic analysis has been difficult due to developmental lethality of Pdp1-null mutants. Here we report the discovery of a mutation that specifically disrupts the Pdp1epsilon isoform. Homozygous Pdp1epsilon mutants are viable and exhibit arrhythmic circadian behavior in constant darkness and also in the presence of light:dark cycles. Importantly, the mutants show diminished expression of CLK and PERIOD (PER) in the central clock cells. In addition, expression of PDF (pigment-dispersing factor) is reduced in a subset of the central clock cells. Loss of Pdp1epsilon also alters the phosphorylation status of the CLK protein and disrupts cyclic expression of a per-luciferase reporter in peripheral clocks under free-running conditions. Transgenic expression of PDP1epsilon in clock neurons of Pdp1epsilon mutants can restore rhythmic circadian behavior. However, transgenic expression of CLK in these mutants rescues the expression of PER in the central clock, but fails to restore behavioral rhythms, suggesting that PDP1epsilon has effects outside the core molecular clock. Together, these data support a model in which PDP1epsilon functions in the central circadian oscillator as well as in the output pathway.
authors.affiliation: Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Xiangzhong
authors.initials: X
authors.lastname: Zheng
authors.forename: Kyunghee
authors.initials: K
authors.lastname: Koh
authors.forename: Mallory
authors.initials: M
authors.lastname: Sowcik
authors.forename: Corinne J
authors.initials: CJ
authors.lastname: Smith
authors.forename: Dechun
authors.initials: D
authors.lastname: Chen
authors.forename: Mark N
authors.initials: MN
authors.lastname: Wu
authors.forename: Amita
authors.initials: A
authors.lastname: Sehgal
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000502:physiology*; D002940:Circadian Rhythm / Q000235:genetics* / Q000502:physiology; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology*; D004331:Drosophila melanogaster / Q000235:genetics; D008297:Male; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D009154:Mutation / Q000235:genetics / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D029721:Drosophila Proteins; C109768:PDP1 protein, Drosophila; D020033:Protein Isoforms