Genetic suppression of the circadian Clock mutation by the melatonin biosynthesis pathway.
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.
Shimomura
Kazuhiro
K
Department of Neurobiology and Physiology, Center for Functional Genomics, and Howard Hughes Medical Institute, Northwestern University, Evanston, IL 60208, USA.
Lowrey
Phillip L
PL
Vitaterna
Martha Hotz
MH
Buhr
Ethan D
ED
Kumar
Vivek
V
Hanna
Peter
P
Omura
Chiaki
C
Izumo
Mariko
M
Low
Sharon S
SS
Barrett
R Keith
RK
LaRue
Silvia I
SI
Green
Carla B
CB
Takahashi
Joseph S
JS
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
D000121:Acetylserotonin O-Methyltransferase; D056926:CLOCK Proteins; C538944:Clock protein, mouse; D047068:Arylalkylamine N-Acetyltransferase; D008550:Melatonin
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