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

• Published in: Frontiers in neuroscience Vol. 17; p. 1181555
• Main Authors: Kobayashi, Riho, Nakane, Shin, Tomita, Jun, Funato, Hiromasa, Yanagisawa, Masashi, Kume, Kazuhiko
• Format: Journal Article
• Language: English
• Published: Lausanne Frontiers Research Foundation 17.08.2023; Frontiers Media S.A
• Subjects: Buses; Circadian rhythm; Circadian rhythms; Daytime; Deficient mutant; Drosophila; Insects; Kinases; Kruskal-Wallis test; Light; Mutation; Neurons; Neuroscience; PDF; Phosphorylation; Protein kinase A; Salt-inducible kinase; Serine; Signal transduction; Sik3; Sleep; United States > US
• ISSN: 1662-453X; 1662-4548; 1662-453X
• DOI: 10.3389/fnins.2023.1181555

Sleep behavior has been observed from non-vertebrates to humans. Sleepy mutation 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 includes 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 by which Sik3-SA increases sleep remains unclear. Here, we found that Sik3-SA overexpression in all neurons increased sleep under both light–dark (LD) conditions and constant dark (DD) conditions in Drosophila . Additionally, overexpression of Sik3-SA only in PDF neurons, which are a cluster of clock neurons regulating the circadian rhythm, increased sleep during subjective daytime while decreasing the amplitude of circadian rhythm. Furthermore, suppressing Sik3-SA overexpression specifically in PDF neurons in flies overexpressing Sik3-SA in all neurons reversed the sleep increase during subjective daytime. These results indicate that Sik3-SA alters the circadian function of PDF neurons and leads to an increase in sleep during subjective daytime under constant dark conditions.