title: Up-regulation of Ras/Raf/ERK1/2 signaling in the spinal cord impairs neural cell migration, neurogenesis, synapse formation, and dendritic spine development.
abstract: BACKGROUND
  The Ras/Raf/ERK1/2 signaling pathway controls many cellular responses such as cell proliferation, migration, differentiation, and death. In the nervous system, emerging evidence also points to a death-promoting role for ERK1/2 in both in vitro and in vivo models of neuronal death. To further investigate how Ras/Raf/ERK1/2 up-regulation may lead to the development of spinal cord injury, we developed a cellular model of Raf/ERK up-regulation by overexpressing c-Raf in cultured spinal cord neurons (SCNs) and dorsal root ganglions (DRGs).
  
  
  METHODS
  DRGs and SCNs were prepared from C57BL/6J mouse pups. DRGs or SCNs were infected with Ad-Raf-1 or Ad-Null adenovirus alone. Cell adhesion assay and cell migration assay were investigated, DiI labeling was employed to examine the effect of the up-regulation of Ras/Raf/ERK1/2 signaling on the dendritic formation of spinal neurons. We used the TO-PRO-3 staining to examine the apoptotic effect of c-Raf on DRGs or SCNs. The effect on the synapse formation of neurons was measured by using immunofluorescence.
  
  
  RESULTS
  We found that Raf/ERK up-regulation stimulates the migration of both SCNs and DRGs, and impairs the formation of excitatory synapses in SCNs. In addition, we found that Raf/ERK up-regulation inhibits the development of mature dendritic spines in SCNs. Investigating the possible mechanisms through which Raf/ERK up-regulation affects the excitatory synapse formation and dendritic spine development, we discovered that Raf/ERK up-regulation suppresses the development and maturation of SCNs.
  
  
  CONCLUSIONS
  The up-regulation of the Raf/ERK signaling pathway may contribute to the pathogenesis of spinal cord injury through both its impairment of the SCN development and causing neural circuit imbalances.
authors.affiliation: Department of Orthopaedics, General Hospital of Tianjin Medical Universtiy, Tianjin 300052, China.
authors.forename: Fu-jiang
authors.initials: FJ
authors.lastname: Cao
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.forename: Xia-wen
authors.initials: XW
authors.lastname: Li
authors.forename: Mazar
authors.initials: M
authors.lastname: Malik
authors.forename: Shi-qing
authors.initials: SQ
authors.lastname: Feng
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology; D049229:Dendritic Spines / Q000378:metabolism / Q000502:physiology*; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000166:cytology; D011247:Pregnancy; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology*; D013569:Synapses / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048490:raf Kinases; D018631:ras Proteins