The Noonan Syndrome-linked Raf1L613V mutation drives increased glial number in the mouse cortex and enhanced learning

PLoS Genet. 2019 Apr 24;15(4):e1008108. doi: 10.1371/journal.pgen.1008108. eCollection 2019 Apr.


RASopathies are a family of related syndromes caused by mutations in regulators of the RAS/Extracellular Regulated Kinase 1/2 (ERK1/2) signaling cascade that often result in neurological deficits. RASopathy mutations in upstream regulatory components, such as NF1, PTPN11/SHP2, and RAS have been well-characterized, but mutation-specific differences in the pathogenesis of nervous system abnormalities remain poorly understood, especially those involving mutations downstream of RAS. Here, we assessed cellular and behavioral phenotypes in mice expressing a Raf1L613V gain-of-function mutation associated with the RASopathy, Noonan Syndrome. We report that Raf1L613V/wt mutants do not exhibit a significantly altered number of excitatory or inhibitory neurons in the cortex. However, we observed a significant increase in the number of specific glial subtypes in the forebrain. The density of GFAP+ astrocytes was significantly increased in the adult Raf1L613V/wt cortex and hippocampus relative to controls. OLIG2+ oligodendrocyte progenitor cells were also increased in number in mutant cortices, but we detected no significant change in myelination. Behavioral analyses revealed no significant changes in voluntary locomotor activity, anxiety-like behavior, or sociability. Surprisingly, Raf1L613V/wt mice performed better than controls in select aspects of the water radial-arm maze, Morris water maze, and cued fear conditioning tasks. Overall, these data show that increased astrocyte and oligodendrocyte progenitor cell (OPC) density in the cortex coincides with enhanced cognition in Raf1L613V/wt mutants and further highlight the distinct effects of RASopathy mutations on nervous system development and function.

Publication types

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

MeSH terms

  • Animals
  • Biomarkers
  • Cerebral Cortex / metabolism*
  • Glial Fibrillary Acidic Protein / metabolism
  • Immunohistochemistry
  • Learning*
  • MAP Kinase Signaling System
  • Maze Learning
  • Memory
  • Mice
  • Mice, Transgenic
  • Mutation*
  • Neuroglia / metabolism*
  • Neurons / metabolism
  • Noonan Syndrome / genetics*
  • Noonan Syndrome / metabolism
  • Noonan Syndrome / psychology*
  • Oligodendroglia / metabolism
  • Proto-Oncogene Proteins c-raf / genetics*
  • Proto-Oncogene Proteins c-raf / metabolism


  • Biomarkers
  • Glial Fibrillary Acidic Protein
  • glial fibrillary astrocytic protein, mouse
  • Proto-Oncogene Proteins c-raf
  • Raf1 protein, human