A phosphorylation-deficient mutant of Sik3, a homolog of Sleepy, alters circadian sleep regulation by PDF neurons in Drosophila

Sleep behavior has been observed from non-vertebrates to humans. Sleepymutation in mice resulted in a notable increase in sleep and was identified as an exon-skipping mutation of the salt-inducible kinase 3 (Sik3)gene, conserved among animals. The skipped exon contains a serine residue that is phosphorylated by protein kinase A. Overexpression of a mutant gene with the conversion of this serine into alanine (Sik3-SA) increased sleep in both mice and the fruit fly Drosophila melanogaster. However, the mechanism how Sik3-SA increases sleep remains unclear. Here, we found, in Drosophila, that Sik3-SA overexpression in all neurons increased sleep both under light-dark (LD) conditions and constant dark (DD) conditions, and its overexpression only in PDF neurons, which is the center of circadian clock, increased sleep during subjective daytime with decreasing the amplitude of circadian rhythm. Moreover, suppression of Sik3-SA overexpression only in PDF neurons in flies overexpressing Sik3-SA in all neurons reversed sleep increase during subjective daytime. In addition, Sik3-SA overexpression in all neurons did not affect the circadian rhythmicity of clock gene expression. These results indicate that Sik3-SA altered the circadian function of PDF neurons and resulted in the increase in sleep during subjective day under constant dark condition.