ERK inhibition rescues defects in fate specification of Nf1-deficient neural progenitors and brain abnormalities

Cell. 2012 Aug 17;150(4):816-30. doi: 10.1016/j.cell.2012.06.034.


Germline mutations in the RAS/ERK signaling pathway underlie several related developmental disorders collectively termed neuro-cardio-facial-cutaneous (NCFC) syndromes. NCFC patients manifest varying degrees of cognitive impairment, but the developmental basis of their brain abnormalities remains largely unknown. Neurofibromatosis type 1 (NF1), an NCFC syndrome, is caused by loss-of-function heterozygous mutations in the NF1 gene, which encodes neurofibromin, a RAS GTPase-activating protein. Here, we show that biallelic Nf1 inactivation promotes Erk-dependent, ectopic Olig2 expression specifically in transit-amplifying progenitors, leading to increased gliogenesis at the expense of neurogenesis in neonatal and adult subventricular zone (SVZ). Nf1-deficient brains exhibit enlarged corpus callosum, a structural defect linked to severe learning deficits in NF1 patients. Strikingly, these NF1-associated developmental defects are rescued by transient treatment with an MEK/ERK inhibitor during neonatal stages. This study reveals a critical role for Nf1 in maintaining postnatal SVZ-derived neurogenesis and identifies a potential therapeutic window for treating NF1-associated brain abnormalities.

Publication types

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

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Brain / pathology*
  • Corpus Callosum / pathology
  • Humans
  • MAP Kinase Signaling System / drug effects*
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / metabolism
  • Neural Stem Cells / pathology*
  • Neurofibromatosis 1 / embryology
  • Neurofibromatosis 1 / metabolism
  • Neurofibromatosis 1 / pathology*
  • Neurofibromin 1 / genetics
  • Neurofibromin 1 / metabolism*
  • Neuroglia / pathology
  • Oligodendrocyte Transcription Factor 2


  • Basic Helix-Loop-Helix Transcription Factors
  • Nerve Tissue Proteins
  • Neurofibromin 1
  • Olig2 protein, mouse
  • Oligodendrocyte Transcription Factor 2