microRNA input into a neural ultradian oscillator controls emergence and timing of alternative cell states

Nat Commun. 2014 Mar 4:5:3399. doi: 10.1038/ncomms4399.

Abstract

Progenitor maintenance, timed differentiation and the potential to enter quiescence are three fundamental processes that underlie the development of any organ system. In the nervous system, progenitor cells show short-period oscillations in the expression of the transcriptional repressor Hes1, while neurons and quiescent progenitors show stable low and high levels of Hes1, respectively. Here we use experimental data to develop a mathematical model of the double-negative interaction between Hes1 and a microRNA, miR-9, with the aim of understanding how cells transition from one state to another. We show that the input of miR-9 into the Hes1 oscillator tunes its oscillatory dynamics, and endows the system with bistability and the ability to measure time to differentiation. Our results suggest that a relatively simple and widespread network of cross-repressive interactions provides a unifying framework for progenitor maintenance, the timing of differentiation and the emergence of alternative cell states.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Cell Line
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Mice
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Models, Theoretical
  • Neural Stem Cells / cytology*
  • Neural Stem Cells / metabolism*
  • Protein Binding
  • Systems Biology
  • Transcription Factor HES-1

Substances

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