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Up-regulation of Ras/Raf/ERK1/2 signaling impairs cultured neuronal cell migration, neurogenesis, synapse formation,

Kun Yang1, Fujiang Cao, Ashfaq M Sheikh

  • 1Department of Neurochemistry, NY State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, New York, NY, 10314, USA.

Brain Structure & Function
|May 5, 2012
PubMed

Insights

Up-regulated Ras/Raf/ERK1/2 signaling impairs neuron development and synapse formation, potentially contributing to autism pathogenesis by disrupting neural circuits.

Area of Science:

  • Neuroscience
  • Cellular Biology
  • Developmental Neuroscience

Background:

  • The Ras/Raf/ERK1/2 pathway regulates crucial cellular functions, including neuronal death.
  • Abnormal apoptosis in the central nervous system is implicated in autism pathogenesis.
  • Genetic studies link chromosome 16 alterations involving MAPK3 (encoding ERK1) to autism.

Purpose of the Study:

  • To investigate the role of up-regulated Ras/Raf/ERK1/2 signaling in autism development.
  • To establish a cellular model for studying Raf/ERK pathway hyperactivity.

Main Methods:

  • Over-expressed c-Raf in cultured cortical neurons (CNs) and cerebellar granule cells (CGCs) to model Raf/ERK up-regulation.
  • Assessed neuronal migration, excitatory synapse formation, and dendritic spine development.
  • Examined the impact of Raf/ERK up-regulation on neuronal development and maturation.

Main Results:

  • Raf/ERK up-regulation promoted CN and CGC migration.
  • Excitatory synapse formation in CNs was impaired by Raf/ERK up-regulation.
  • Dendritic spine development and maturation in CNs were inhibited.
  • Overall suppression of CN development and maturation was observed.

Conclusions:

  • Up-regulation of the Raf/ERK signaling pathway may contribute to autism pathogenesis.
  • This pathway's hyperactivity impairs cortical neuron development.
  • Neural circuit imbalances resulting from Raf/ERK up-regulation may play a role in autism.

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