MicroRNA-9 Modulates Hes1 ultradian oscillations by forming a double-negative feedback loop

Cell Rep. 2012 Jul 26;2(1):10-8. doi: 10.1016/j.celrep.2012.05.017. Epub 2012 Jun 28.


Short-period (ultradian) oscillations of Hes1, a Notch signaling effector, are essential for maintaining neural progenitors in a proliferative state, while constitutive downregulation of Hes1 leads to neuronal differentiation. Hes1 oscillations are driven by autorepression, coupled with high instability of the protein and mRNA. It is unknown how Hes1 mRNA stability is controlled and furthermore, how cells exit oscillations in order to differentiate. Here, we identify a microRNA, miR-9, as a component of ultradian oscillations. We show that miR-9 controls the stability of Hes1 mRNA and that both miR-9 overexpression and lack of miR-9 dampens Hes1 oscillations. Reciprocally, Hes1 represses the transcription of miR-9, resulting in out-of-phase oscillations. However, unlike the primary transcript, mature miR-9 is very stable and thus accumulates over time. Given that raising miR-9 levels leads to dampening of oscillations, these findings provide support for a self-limiting mechanism whereby cells might terminate Hes1 oscillations and differentiate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activity Cycles / genetics*
  • Activity Cycles / physiology
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Biological Clocks / genetics*
  • Cells, Cultured
  • Feedback, Physiological / physiology
  • Gene Expression Regulation
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • MicroRNAs / physiology*
  • Models, Biological
  • RNA Interference / physiology
  • RNA, Messenger / metabolism
  • Transcription Factor HES-1
  • Transcription, Genetic / genetics


  • Basic Helix-Loop-Helix Transcription Factors
  • Hes1 protein, mouse
  • Homeodomain Proteins
  • MIRN9 microRNA, mouse
  • MicroRNAs
  • RNA, Messenger
  • Transcription Factor HES-1