title: dyschronic, a Drosophila homolog of a deaf-blindness gene, regulates circadian output and Slowpoke channels.
abstract: Many aspects of behavior and physiology are under circadian control. In Drosophila, the molecular clock that regulates rhythmic patterns of behavior has been extensively characterized. In contrast, genetic loci involved in linking the clock to alterations in motor activity have remained elusive. In a forward-genetic screen, we uncovered a new component of the circadian output pathway, which we have termed dyschronic (dysc). dysc mutants exhibit arrhythmic locomotor behavior, yet their eclosion rhythms are normal and clock protein cycling remains intact. Intriguingly, dysc is the closest Drosophila homolog of whirlin, a gene linked to type II Usher syndrome, the leading cause of deaf-blindness in humans. Whirlin and other Usher proteins are expressed in the mammalian central nervous system, yet their function in the CNS has not been investigated. We show that DYSC is expressed in major neuronal tracts and regulates expression of the calcium-activated potassium channel SLOWPOKE (SLO), an ion channel also required in the circadian output pathway. SLO and DYSC are co-localized in the brain and control each other's expression post-transcriptionally. Co-immunoprecipitation experiments demonstrate they form a complex, suggesting they regulate each other through protein-protein interaction. Furthermore, electrophysiological recordings of neurons in the adult brain show that SLO-dependent currents are greatly reduced in dysc mutants. Our work identifies a Drosophila homolog of a deaf-blindness gene as a new component of the circadian output pathway and an important regulator of ion channel expression, and suggests novel roles for Usher proteins in the mammalian nervous system.
authors.affiliation: Department of Neuroscience, Farber Institute of Neuroscience, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: James E C
authors.initials: JE
authors.lastname: Jepson
authors.forename: Mohammad
authors.initials: M
authors.lastname: Shahidullah
authors.forename: Angelique
authors.initials: A
authors.lastname: Lamaze
authors.forename: Drew
authors.initials: D
authors.lastname: Peterson
authors.forename: Huihui
authors.initials: H
authors.lastname: Pan
authors.forename: Kyunghee
authors.initials: K
authors.lastname: Koh
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism; D002940:Circadian Rhythm / Q000235:genetics*; D054062:Deaf-Blind Disorders / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins; D009043:Motor Activity / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D060066:Protein Interaction Maps / Q000235:genetics
chemical_list: C512669:Clrn1 protein, rat; D029721:Drosophila Proteins; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008565:Membrane Proteins; C494844:slo protein, Drosophila