FOXC1 modulates MYOC secretion through regulation of the exocytic proteins RAB3GAP1, RAB3GAP2 and SNAP25

PLoS One. 2017 Jun 2;12(6):e0178518. doi: 10.1371/journal.pone.0178518. eCollection 2017.

Abstract

The neurodegenerative disease glaucoma is one of the leading causes of blindness in the world. Glaucoma is characterized by progressive visual field loss caused by retinal ganglion cell (RGC) death. Both surgical glaucoma treatments and medications are available, however, they only halt glaucoma progression and are unable to reverse damage. Furthermore, many patients do not respond well to treatments. It is therefore important to better understand the mechanisms involved in glaucoma pathogenesis. Patients with Axenfeld-Rieger syndrome (ARS) offer important insight into glaucoma progression. ARS patients are at 50% risk of developing early onset glaucoma and respond poorly to treatments, even when surgical treatments are combined with medications. Mutations in the transcription factor FOXC1 cause ARS. Alterations in FOXC1 levels cause ocular malformations and disrupt stress response in ocular tissues, thereby contributing to glaucoma progression. In this study, using biochemical and molecular techniques, we show that FOXC1 regulates the expression of RAB3GAP1, RAB3GAP2 and SNAP25, three genes with central roles in both exocytosis and endocytosis, responsible for extracellular trafficking. FOXC1 positively regulates RAB3GAP1 and RAB3GAP2, while either increase or decrease in FOXC1 levels beyond its normal range results in decreased SNAP25. In addition, we found that FOXC1 regulation of RAB3GAP1, RAB3GAP2 and SNAP25 affects secretion of Myocilin (MYOC), a protein associated with juvenile onset glaucoma and steroid-induced glaucoma. The present work reveals that FOXC1 is an important regulator of exocytosis and establishes a new link between FOXC1 and MYOC-associated glaucoma.

MeSH terms

  • Cytoskeletal Proteins / metabolism*
  • Exocytosis*
  • Eye Proteins / metabolism*
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / physiology*
  • Gene Knockdown Techniques
  • Glycoproteins / metabolism*
  • HeLa Cells
  • Humans
  • Luciferases / genetics
  • RNA, Messenger / genetics
  • Synaptosomal-Associated Protein 25 / genetics
  • Synaptosomal-Associated Protein 25 / physiology*
  • Transcriptional Activation
  • rab3 GTP-Binding Proteins / genetics
  • rab3 GTP-Binding Proteins / physiology*

Substances

  • Cytoskeletal Proteins
  • Eye Proteins
  • FOXC1 protein, human
  • Forkhead Transcription Factors
  • Glycoproteins
  • RAB3GAP2 protein, human
  • RNA, Messenger
  • SNAP25 protein, human
  • Synaptosomal-Associated Protein 25
  • trabecular meshwork-induced glucocorticoid response protein
  • Luciferases
  • RAB3GAP1 protein, human
  • rab3 GTP-Binding Proteins

Grant support

Canadian Institutes of Health Research (http://cihr-irsc.gc.ca/); Grant no. G118160216, to M.A.W.