Myocilin expression is regulated by retinoic acid in the trabecular meshwork-derived cellular environment

Exp Eye Res. 2017 Feb:155:91-98. doi: 10.1016/j.exer.2017.01.006. Epub 2017 Jan 30.

Abstract

Glaucoma is the leading cause of irreversible blindness and is usually classified as angle closure and open angle glaucoma (OAG). Primary open angle glaucoma represents the most frequent clinical presentation leading to ganglion cell death and optic nerve degeneration as a main consequence of an intraocular pressure' (IOP) increase. The mechanisms of this IOP increase in such pathology remain unclear but one protein called Myocilin could be a part of the puzzle in the trabecular meshwork (TM). Previously described to be transcriptionally regulated by glucocorticoids, the comprehension of the trabecular regulation of Myocilin' expression has only weakly progressed since 15 years. Due to the essential molecular and cellular implications of retinoids' pathway in eye development and physiology, we investigate the potential role of the retinoic acid in such regulation and expression. This study demonstrates that the global retinoids signaling machinery is present in immortalized TM cells and that Myocilin (MYOC) expression is upregulated by retinoic acid alone or combined with a glucocorticoid co-treatment. This regulation by retinoic acid acts through the MYOC promoter which contains a critical cluster of four retinoic acid responsive elements (RAREs), with the RARE-DR2 presenting the strongest effect and binding the RARα/RXRα heterodimer. All together, these results open up new perspectives for the molecular understanding glaucoma pathophysiology and provide further actionable clues on Myocilin gene regulation.

Keywords: Gene regulation; Glaucoma; Myocilin; Retinoic acid; Retinoids; Trabecular meshwork.

MeSH terms

  • Blotting, Western
  • Cells, Cultured
  • Cytoskeletal Proteins / biosynthesis
  • Cytoskeletal Proteins / drug effects
  • Cytoskeletal Proteins / genetics*
  • Eye Proteins / biosynthesis
  • Eye Proteins / drug effects
  • Eye Proteins / genetics*
  • Gene Expression Regulation*
  • Glaucoma, Open-Angle / drug therapy
  • Glaucoma, Open-Angle / genetics*
  • Glaucoma, Open-Angle / metabolism
  • Glycoproteins / biosynthesis
  • Glycoproteins / drug effects
  • Glycoproteins / genetics*
  • Humans
  • Immunohistochemistry
  • Intraocular Pressure / physiology
  • Keratolytic Agents / pharmacology
  • RNA / genetics*
  • Real-Time Polymerase Chain Reaction
  • Trabecular Meshwork / drug effects
  • Trabecular Meshwork / metabolism*
  • Trabecular Meshwork / pathology
  • Tretinoin / pharmacology*

Substances

  • Cytoskeletal Proteins
  • Eye Proteins
  • Glycoproteins
  • Keratolytic Agents
  • trabecular meshwork-induced glucocorticoid response protein
  • Tretinoin
  • RNA