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

Abstract

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.

Activation of the High-Mobility Group Box 1 Protein-Receptor for Advanced Glycation End-Products Signaling Pathway in Rats During Neurogenesis After Intracerebral Hemorrhage

“…24 RAGE signaling modulates neurotrophin-dependent neurite outgrowth in cultured adult sensory neurons 25 and promotes differentiation of neuronal cells. 26 The present study adds to the number of pathways, both physiological and pathophysiological, that the HMGB1-RAGE axis helps to regulate.…”

Pattern recognition receptors in chronic pain: Mechanisms and therapeutic implications

“…Consistently, in vitro studies using mouse hippocampal neuronal cultures or human brain-derived neuronal cell lines show that RAGE can only be detected in differentiating cells or progenitor cells (Kim et al, 2012;Meneghini et al, 2013;Piras et al, 2014). The in vivo evidence regarding the expression of PRRs in neurons in the CNS is scarce.…”

Axonal Amphoterin mRNA Is Regulated by Translational Control and Enhances Axon Outgrowth

“…Neurons are extremely polarized, with cytoplasmic processes in some mammalian species extending to more than 1 m from a cell body that is most often Ͻ100 m in diameter. The mechanisms for spatial control of neuronal translation have been best characterized in dendrites, with trans-synaptic stimuli triggering dendritic protein synthesis (Liu-Yesucevitz et al, 2011). Axonal processes typically extend much longer distances than dendrites, potentially requiring even greater autonomy gained by localized protein synthesis.…”

“…Exogenous amphoterin also augments neurotrophic factor driven axon growth from adult DRG neurons and this effect requires expression of RAGE (Saleh et al, 2013). RAGE has been shown to localize to distal neurites and its downstream signaling activates pathways associated with neurite growth (Huttunen et al, 2002;Rong et al, 2004a;Kim et al, 2012;Saleh et al, 2013). Therefore, RAGE is well positioned to exert the growth-promoting effects of the locally synthesized amphoterin that we have studied here.…”