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DEC2 modulates orexin expression and regulates sleep.

Arisa Hirano1, Pei-Ken Hsu1, Luoying Zhang1

  • 1Department of Neurology, University of California, San Francisco, CA 94143.

Proceedings of the National Academy of Sciences of the United States of America
|March 14, 2018
PubMed
Summary
This summary is machine-generated.

Natural short sleep is linked to a mutation in the DEC2 gene. This mutation increases orexin (hypocretin) expression, a key factor in maintaining arousal and regulating sleep duration.

Keywords:
behaviorgeneticsmouse modelsleep

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Area of Science:

  • Genetics
  • Neuroscience
  • Sleep Medicine

Background:

  • Adequate sleep is crucial for overall health.
  • A mutation in the human DEC2 gene (BHLHE41) is associated with familial natural short sleep.
  • The precise role of DEC2 in sleep regulation was previously unclear.

Purpose of the Study:

  • To investigate the molecular mechanism by which the DEC2 gene mutation affects sleep regulation.
  • To explore the relationship between DEC2 and the orexin/hypocretin system.

Main Methods:

  • Utilized a mouse model expressing a mutant human DEC2 transgene (hDEC2-P384R).
  • Assessed prepro-orexin (hypocretin) gene expression in the mutant mouse model.
  • Performed cell culture experiments to examine DEC2's effect on the prepro-orexin promoter.
  • Investigated the impact of an orexin receptor antagonist on the behavior of mutant mice.

Main Results:

  • The mutant hDEC2 transgene led to increased prepro-orexin (hypocretin) gene expression.
  • DEC2 acts as a repressor of the prepro-orexin gene promoter via E-box elements.
  • The P384R mutation in DEC2 reduced its repressor activity, enhancing orexin expression.
  • Orexin receptor antagonism attenuated the reduced immobility time in mutant mice.

Conclusions:

  • DEC2 regulates sleep duration, partly through modulation of the neuropeptide hormone orexin.
  • The DEC2-P384R mutation impairs orexin regulation, contributing to short sleep traits.
  • This study elucidates a novel pathway linking DEC2, orexin, and sleep-wake regulation.