title: Genetic suppression of the circadian Clock mutation by the melatonin biosynthesis pathway.
abstract: Most laboratory mouse strains including C57BL/6J do not produce detectable levels of pineal melatonin owing to deficits in enzymatic activity of arylalkylamine N-acetyltransferase (AANAT) and N-acetylserotonin O-methyl transferase (ASMT), two enzymes necessary for melatonin biosynthesis. Here we report that alleles segregating at these two loci in C3H/HeJ mice, an inbred strain producing melatonin, suppress the circadian period-lengthening effect of the Clock mutation. Through a functional mapping approach, we localize mouse Asmt to chromosome X and show that it, and the Aanat locus on chromosome 11, are significantly associated with pineal melatonin levels. Treatment of suprachiasmatic nucleus (SCN) explant cultures from Period2(Luciferase) (Per2(Luc)) Clock/+ reporter mice with melatonin, or the melatonin agonist, ramelteon, phenocopies the genetic suppression of the Clock mutant phenotype observed in living animals. These results demonstrate that melatonin suppresses the Clock/+ mutant phenotype and interacts with Clock to affect the mammalian circadian system.
authors.affiliation: Department of Neurobiology and Physiology, Center for Functional Genomics, and Howard Hughes Medical Institute, Northwestern University, Evanston, IL 60208, USA.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shimomura
authors.forename: Phillip L
authors.initials: PL
authors.lastname: Lowrey
authors.forename: Martha Hotz
authors.initials: MH
authors.lastname: Vitaterna
authors.forename: Ethan D
authors.initials: ED
authors.lastname: Buhr
authors.forename: Vivek
authors.initials: V
authors.lastname: Kumar
authors.forename: Peter
authors.initials: P
authors.lastname: Hanna
authors.forename: Chiaki
authors.initials: C
authors.lastname: Omura
authors.forename: Mariko
authors.initials: M
authors.lastname: Izumo
authors.forename: Sharon S
authors.initials: SS
authors.lastname: Low
authors.forename: R Keith
authors.initials: RK
authors.lastname: Barrett
authors.forename: Silvia I
authors.initials: SI
authors.lastname: LaRue
authors.forename: Carla B
authors.initials: CB
authors.lastname: Green
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Takahashi
mesh_terms: D000121:Acetylserotonin O-Methyltransferase / Q000378:metabolism; D000818:Animals; D047068:Arylalkylamine N-Acetyltransferase / Q000378:metabolism; D001522:Behavior, Animal; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism*; D002875:Chromosomes; D002940:Circadian Rhythm; D015536:Down-Regulation; D008550:Melatonin / Q000096:biosynthesis*; D051379:Mice; D008809:Mice, Inbred C3H; D009154:Mutation; D010641:Phenotype
chemical_list: D000121:Acetylserotonin O-Methyltransferase; D056926:CLOCK Proteins; C538944:Clock protein, mouse; D047068:Arylalkylamine N-Acetyltransferase; D008550:Melatonin
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