TY - JOUR
T1 - Genetic suppression of the circadian Clock mutation by the melatonin biosynthesis pathway
AU - Shimomura, Kazuhiro
AU - Lowrey, Phillip L.
AU - Vitaterna, Martha Hotz
AU - Buhr, Ethan D.
AU - Kumar, Vivek
AU - Hanna, Peter
AU - Omura, Chiaki
AU - Izumo, Mariko
AU - Low, Sharon S.
AU - Barrett, R. Keith
AU - LaRue, Silvia I.
AU - Green, Carla B.
AU - Takahashi, Joseph S.
PY - 2010/5/4
Y1 - 2010/5/4
N2 - 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 Period2Luciferase (Per2Luc) 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.
AB - 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 Period2Luciferase (Per2Luc) 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.
KW - Arylalkylamine N-acetyltransferase
KW - Clock gene
KW - N-acetylserotonin O-methytransferase
KW - Suprachiasmatic nucleus
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U2 - 10.1073/pnas.1004368107
DO - 10.1073/pnas.1004368107
M3 - Article
C2 - 20404168
AN - SCOPUS:77952411362
SN - 0027-8424
VL - 107
SP - 8399
EP - 8403
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 18
ER -