The role of receptor for advanced glycation end products (RAGE) in neuronal differentiation

J Neurosci Res. 2012 Jun;90(6):1136-47. doi: 10.1002/jnr.23014. Epub 2012 Feb 16.


The receptor for advanced glycation end products (RAGE) is a multiligand receptor protein thought to play an important role in neuronal differentiation. RAGE can bind a number of ligands and activate a variety of signalling pathways that lead to diverse downstream effects. Amphoterin and S100B are endogenous ligands, the interaction of which with RAGE is known to be involved in defined physiological processes. The present study investigated the spatiotemporal pattern of the expression for RAGE and its ligands, amphoterin and S100B, during neuronal differentiation of NT2/D1 cells. In this study, all three proteins were shown to increase with progression of neuronal differentiation as determined by Western blotting, raising the possibility that both amphoterin and S100B may interact with RAGE and have important functions during the process of cell differentiation. Moreover, blocking the activation of RAGE with neutralizing antibody in the presence of retinoic acid disrupted the progression of normal neuronal differentiation. Immunocytochemistry (ICC) studies showed that amphoterin partially colocalized with RAGE within differentiating NT2 cells, whereas S100B showed a high degree of colocalization. This result suggests that S100B is more likely to be the principal ligand for RAGE during the differentiation process and that RAGE and amphoterin might have both independent and combined roles. Moreover, RAGE was expressed only in cells that were committed to a neuronal phenotype, suggesting direct involvement of RAGE in mediating cellular changes within differentiating neuronal cells. Further detailed studies are now required to characterize fully the role of RAGE during the neuronal differentiation period.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies / pharmacology
  • Antineoplastic Agents / pharmacology
  • Carcinoma / pathology
  • Cell Cycle / drug effects
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology*
  • Cell Line, Tumor
  • HMGB1 Protein / genetics
  • HMGB1 Protein / metabolism
  • Humans
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism
  • Neurons / drug effects
  • Neurons / physiology*
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / immunology
  • Receptors, Immunologic / physiology*
  • S100 Calcium Binding Protein beta Subunit
  • S100 Proteins / genetics
  • S100 Proteins / metabolism
  • Tretinoin / pharmacology
  • Up-Regulation / drug effects
  • Up-Regulation / physiology


  • Antibodies
  • Antineoplastic Agents
  • HMGB1 Protein
  • Nerve Growth Factors
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • S100 Calcium Binding Protein beta Subunit
  • S100 Proteins
  • S100B protein, human
  • Tretinoin