Mir-17-3p controls spinal neural progenitor patterning by regulating Olig2/Irx3 cross-repressive loop

Neuron. 2011 Feb 24;69(4):721-35. doi: 10.1016/j.neuron.2011.01.014.

Abstract

Neural patterning relies on transcriptional cross-repressive interactions that ensure unequivocal assignment of neural progenitor identity to proliferating cells. Progenitors of spinal motor neurons (pMN) and V2 interneurons (p2) are specified by a pair of cross-repressive transcription factors, Olig2 and Irx3. Lineage tracing revealed that many p2 progenitors transiently express the pMN marker Olig2 during spinal cord development. Here we demonstrate that the repression of Olig2 in p2 domain is controlled by mir-17-3p microRNA-mediated silencing of Olig2 mRNA. Mice lacking all microRNAs or just the mir-17∼92 cluster manifest a dorsal shift in pMN/p2 boundary and impairment in the production of V2 interneurons. Our findings suggest that microRNA-mediated repression of Olig2 mRNA plays a critical role during the patterning of ventral spinal progenitor domains by shifting the balance of cross-repressive interactions between Olig2 and Irx3 transcription factors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism
  • Dose-Response Relationship, Drug
  • Doxycycline / pharmacology
  • Embryo, Mammalian
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism
  • Estrogen Antagonists / pharmacology
  • Gene Expression Regulation, Developmental / drug effects
  • Gene Expression Regulation, Developmental / genetics
  • Gene Expression Regulation, Developmental / physiology*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Interneurons / metabolism
  • Luminescent Proteins / genetics
  • Macromolecular Substances / metabolism
  • Mice
  • Mice, Transgenic
  • MicroRNAs / physiology*
  • Models, Biological
  • Motor Neurons / metabolism
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / physiology*
  • Oligodendrocyte Transcription Factor 2
  • Proteins / genetics
  • RNA, Untranslated
  • Ribonuclease III
  • Spinal Cord / cytology*
  • Structure-Activity Relationship
  • Tamoxifen / analogs & derivatives
  • Tamoxifen / pharmacology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transfection / methods

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Estrogen Antagonists
  • Gt(ROSA)26Sor non-coding RNA, mouse
  • Homeodomain Proteins
  • Irx3 protein, mouse
  • Luminescent Proteins
  • Macromolecular Substances
  • MicroRNAs
  • Mirn17 microRNA, mouse
  • Nerve Tissue Proteins
  • Nkx6-1 protein, mouse
  • Olig2 protein, mouse
  • Oligodendrocyte Transcription Factor 2
  • Proteins
  • RNA, Untranslated
  • Transcription Factors
  • Tamoxifen
  • afimoxifene
  • Endoribonucleases
  • Dicer1 protein, mouse
  • Ribonuclease III
  • DEAD-box RNA Helicases
  • Doxycycline