A unilateral negative feedback loop between miR-200 microRNAs and Sox2/E2F3 controls neural progenitor cell-cycle exit and differentiation

J Neurosci. 2012 Sep 19;32(38):13292-308. doi: 10.1523/JNEUROSCI.2124-12.2012.

Abstract

MicroRNAs have emerged as key posttranscriptional regulators of gene expression during vertebrate development. We show that the miR-200 family plays a crucial role for the proper generation and survival of ventral neuronal populations in the murine midbrain/hindbrain region, including midbrain dopaminergic neurons, by directly targeting the pluripotency factor Sox2 and the cell-cycle regulator E2F3 in neural stem/progenitor cells. The lack of a negative regulation of Sox2 and E2F3 by miR-200 in conditional Dicer1 mutants (En1(+/Cre); Dicer1(flox/flox) mice) and after miR-200 knockdown in vitro leads to a strongly reduced cell-cycle exit and neuronal differentiation of ventral midbrain/hindbrain (vMH) neural progenitors, whereas the opposite effect is seen after miR-200 overexpression in primary vMH cells. Expression of miR-200 is in turn directly regulated by Sox2 and E2F3, thereby establishing a unilateral negative feedback loop required for the cell-cycle exit and neuronal differentiation of neural stem/progenitor cells. Our findings suggest that the posttranscriptional regulation of Sox2 and E2F3 by miR-200 family members might be a general mechanism to control the transition from a pluripotent/multipotent stem/progenitor cell to a postmitotic and more differentiated cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Cell Count
  • Cell Cycle / genetics
  • Cell Cycle / physiology*
  • Cell Death / genetics
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology*
  • Cells, Cultured
  • Chlorocebus aethiops
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism
  • Deoxyuridine / analogs & derivatives
  • Deoxyuridine / metabolism
  • E2F3 Transcription Factor / genetics
  • E2F3 Transcription Factor / metabolism*
  • Embryo, Mammalian
  • Female
  • Gene Expression Regulation, Developmental / genetics
  • Gene Expression Regulation, Developmental / physiology*
  • Green Fluorescent Proteins / genetics
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Male
  • Mesencephalon / cytology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Models, Biological
  • Mutation / genetics
  • Nerve Tissue Proteins / metabolism
  • Neural Stem Cells / physiology*
  • Rhombencephalon / cytology
  • Ribonuclease III / genetics
  • Ribonuclease III / metabolism
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism*
  • Serotonin / metabolism
  • Signal Transduction / genetics
  • Transcription Factor Brn-3A / metabolism
  • Transcription Factors / metabolism
  • Transfection

Substances

  • E2F3 Transcription Factor
  • E2f3 protein, mouse
  • En1 protein, mouse
  • Homeodomain Proteins
  • MicroRNAs
  • Mirn200 microRNA, mouse
  • Nerve Tissue Proteins
  • Pou4f1 protein, mouse
  • SOXB1 Transcription Factors
  • Sox2 protein, mouse
  • Transcription Factor Brn-3A
  • Transcription Factors
  • enhanced green fluorescent protein
  • homeobox protein PITX3
  • Green Fluorescent Proteins
  • Serotonin
  • Dicer1 protein, mouse
  • Ribonuclease III
  • DEAD-box RNA Helicases
  • 5-ethynyl-2'-deoxyuridine
  • Deoxyuridine