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A conditional Smg6 mutant mouse model reveals circadian clock regulation through the nonsense-mediated mRNA decay

Georgia Katsioudi1, René Dreos1, Enes S Arpa1

  • 1Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.

Science Advances
|January 13, 2023
PubMed

Insights

Nonsense-mediated mRNA decay (NMD) impacts circadian clock function. Down-regulating NMD lengthens circadian periods and alters daily mRNA patterns, revealing new roles for NMD in mammalian physiology.

Area of Science:

  • Molecular Biology
  • Chronobiology
  • Genetics

Background:

  • Nonsense-mediated mRNA decay (NMD) is a key surveillance pathway degrading aberrant transcripts.
  • While NMD's role in mRNA quality control is established, its physiological functions in vivo are less understood.
  • The circadian clock relies on rapid mRNA turnover, suggesting potential NMD involvement.

Purpose of the Study:

  • To investigate the in vivo physiological roles of NMD in mammalian systems.
  • To determine the impact of NMD on the circadian clock.
  • To identify specific NMD targets within circadian rhythm pathways.

Main Methods:

  • Generation of a conditional mouse model to modulate the NMD effector SMG6.
  • Analysis of circadian clock function (period length) in liver and fibroblast cells.
  • Transcriptome-wide analysis of mRNA accumulation patterns and NMD targets.

Main Results:

  • NMD down-regulation led to significant lengthening of free-running circadian periods in liver and fibroblast clocks.
  • Direct NMD regulation of Cry2 mRNA, a crucial component of the circadian feedback loop, was identified.
  • Transcriptome-wide analysis revealed altered daily mRNA accumulation in the liver and impaired food entrainment response.

Conclusions:

  • NMD plays a significant role in regulating circadian clock function in mammals.
  • NMD directly influences the stability of key circadian clock genes like Cry2.
  • These findings expand the known scope of NMD's regulatory functions in mammalian gene expression and physiology.

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