miR-137 forms a regulatory loop with nuclear receptor TLX and LSD1 in neural stem cells

Nat Commun. 2011 Nov 8;2:529. doi: 10.1038/ncomms1532.

Abstract

miR-137 is a brain-enriched microRNA. Its role in neural development remains unknown. Here we show that miR-137 has an essential role in controlling embryonic neural stem cell fate determination. miR-137 negatively regulates cell proliferation and accelerates neural differentiation of embryonic neural stem cells. In addition, we show that the histone lysine-specific demethylase 1 (LSD1), a transcriptional co-repressor of nuclear receptor TLX, is a downstream target of miR-137. In utero electroporation of miR-137 in embryonic mouse brains led to premature differentiation and outward migration of the transfected cells. Introducing a LSD1 expression vector lacking the miR-137 recognition site rescued miR-137-induced precocious differentiation. Furthermore, we demonstrate that TLX, an essential regulator of neural stem cell self-renewal, represses the expression of miR-137 by recruiting LSD1 to the genomic regions of miR-137. Thus, miR-137 forms a feedback regulatory loop with TLX and LSD1 to control the dynamics between neural stem cell proliferation and differentiation during neural development.

Publication types

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

MeSH terms

  • Animals
  • Blotting, Western
  • Brain / cytology
  • Brain / metabolism
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Cell Proliferation
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Electroporation
  • Female
  • Histone Demethylases
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Neural Stem Cells / cytology*
  • Neural Stem Cells / metabolism*
  • Oxidoreductases, N-Demethylating / genetics
  • Oxidoreductases, N-Demethylating / metabolism*
  • Pregnancy
  • Protein Binding / genetics
  • Protein Binding / physiology
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*

Substances

  • MIRN137 microRNA, mouse
  • MicroRNAs
  • Nr2e1 protein, mouse
  • Receptors, Cytoplasmic and Nuclear
  • Histone Demethylases
  • KDM1a protein, mouse
  • Oxidoreductases, N-Demethylating