Genetic suppression of the circadian Clock mutation by the melatonin biosynthesis pathway

Kazuhiro Shimomura, Phillip L. Lowrey, Martha Hotz Vitaterna, Ethan D. Buhr, Vivek Kumar, Peter Hanna, Chiaki Omura, Mariko Izumo, Sharon S. Low, R. Keith Barrett, Silvia I. LaRue, Carla B. Green, Joseph S. Takahashi

Research output: Contribution to journalArticle

41 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)8399-8403
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number18
DOIs
StatePublished - May 4 2010

Keywords

  • Arylalkylamine N-acetyltransferase
  • Clock gene
  • N-acetylserotonin O-methytransferase
  • Suprachiasmatic nucleus

ASJC Scopus subject areas

  • General

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  • Cite this

    Shimomura, K., Lowrey, P. L., Vitaterna, M. H., Buhr, E. D., Kumar, V., Hanna, P., Omura, C., Izumo, M., Low, S. S., Barrett, R. K., LaRue, S. I., Green, C. B., & Takahashi, J. S. (2010). Genetic suppression of the circadian Clock mutation by the melatonin biosynthesis pathway. Proceedings of the National Academy of Sciences of the United States of America, 107(18), 8399-8403. https://doi.org/10.1073/pnas.1004368107