Abstract
The Aryl hydrocarbon Receptor(AhR) is among the most important receptors which bind pollutants; however it also regulates signaling pathways independently of such exposure. We previously demonstrated that AhR is expressed during development of the central nervous system(CNS) and that its deletion leads to the occurrence of a congenital nystagmus. Objectives of the present study are to decipher the origin of these deficits, and to identify the role of the AhR in the development of the CNS. We show that the AhR-knockout phenotype develops during early infancy together with deficits in visual-information-processing which are associated with an altered optic nerve myelin sheath, which exhibits modifications in its lipid composition and in the expression of myelin-associated-glycoprotein(MAG), a cell adhesion molecule involved in myelin-maintenance and glia-axon interaction. In addition, we show that the expression of pro-inflammatory cytokines is increased in the impaired optic nerve and confirm that inflammation is causally related with an AhR-dependent decreased expression of MAG. Overall, our findings demonstrate the role of the AhR as a physiological regulator of myelination and inflammatory processes in the developing CNS. It identifies a mechanism by which environmental pollutants might influence CNS myelination and suggest AhR as a relevant drug target for demyelinating diseases.
Highlights
The Aryl hydrocarbon Receptor (AhR), a ligand-activated transcription factor, belongs to the basic-Helix-Loop-Helix/Per-ARNT-Sim family that regulates detoxification[1]
At P26, the nystagmus was present in all AhR-KO mice, while it was never observed in WT-control mice
Considering that nystagmus is often associated with visual deficits, we recorded visual evoked potentials (VEPs) from the primary visual cortex; we found that amplitudes were lower in adult AhR-KO vs. WT mice (Fig. 1d-left), indicating a deficit in the integration of visual information
Summary
The Aryl hydrocarbon Receptor (AhR), a ligand-activated transcription factor, belongs to the basic-Helix-Loop-Helix/Per-ARNT-Sim family that regulates detoxification[1]. The diagnosis and the characterization of the nystagmus have major clinical implications because it represents a predictive symptom of major central nervous system pathologies, including multiple sclerosis or Pelizaeus-Merzbacher disease[10,11,12,13]. We have previously shown that the origin of the nystagmus was not vestibular neither cerebellar, while the AhR was expressed in the eye during mice development. We have extended our research at the cellular and molecular levels focusing our efforts on different characteristics of the visual circuitry, mostly anatomical and structural, and showed that the disease was related to a significant demyelination of the optic nerves in the AhR-KO mice. Our study first reports the role of the AhR in the pathogenesis of demyelinating diseases associated with inflammation such as optic neuritis or multiple sclerosis, providing new avenues for the understanding and the treatment of nystagmus-related pathologies
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