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The Journal of Neuroscience, September 2, 2009, 29(35):10920-10927; doi:10.1523/JNEUROSCI.2133-09.2009

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Cellular/Molecular
An Isoform-Specific Mutant Reveals a Role of PDP1 in the Circadian Oscillator

Xiangzhong Zheng,^1 * Kyunghee Koh,^1 * Mallory Sowcik,² Corinne J. Smith,² Dechun Chen,¹ Mark N. Wu,³ and Amita Sehgal^1,2

¹Department of Neuroscience, ²Howard Hughes Medical Institute, and ³Department of Neurology, Division of Sleep Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Correspondence should be addressed to Amita Sehgal, 232 Stemmler Hall, Department of Neuroscience, University of Pennsylvania Medical School, Philadelphia, PA 19104. Email: amita{at}mail.med.upenn.edu

The Drosophila PAR domain protein 1 (Pdp1) gene encodes a transcription factor with multiple functions. One isoform, PDP1, was proposed to be an essential activator of the core clock gene, Clock (Clk). However, a central clock function for PDP1 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 Pdp1 isoform. Homozygous Pdp1 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 Pdp1 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 PDP1 in clock neurons of Pdp1 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 PDP1 has effects outside the core molecular clock. Together, these data support a model in which PDP1 functions in the central circadian oscillator as well as in the output pathway.

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Received May 6, 2009; revised July 17, 2009; accepted July 20, 2009.

Correspondence should be addressed to Amita Sehgal, 232 Stemmler Hall, Department of Neuroscience, University of Pennsylvania Medical School, Philadelphia, PA 19104. Email: amita{at}mail.med.upenn.edu

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