Conditional Loss of the Exocyst Component Exoc5 in Retinal Pigment Epithelium (RPE) Results in RPE Dysfunction, Photoreceptor Cell Degeneration, and Decreased Visual Function

Int J Mol Sci. 2021 May 11;22(10):5083. doi: 10.3390/ijms22105083.

Abstract

To characterize the mechanisms by which the highly conserved exocyst trafficking complex regulates eye physiology in zebrafish and mice, we focused on Exoc5 (also known as sec10), a central exocyst component. We analyzed both exoc5 zebrafish mutants and retinal pigmented epithelium (RPE)-specific Exoc5 knockout mice. Exoc5 is present in both the non-pigmented epithelium of the ciliary body and in the RPE. In this study, we set out to establish an animal model to study the mechanisms underlying the ocular phenotype and to establish if loss of visual function is induced by postnatal RPE Exoc5-deficiency. Exoc5-/- zebrafish had smaller eyes, with decreased number of melanocytes in the RPE and shorter photoreceptor outer segments. At 3.5 days post-fertilization, loss of rod and cone opsins were observed in zebrafish exoc5 mutants. Mice with postnatal RPE-specific loss of Exoc5 showed retinal thinning associated with compromised visual function and loss of visual photoreceptor pigments. Abnormal levels of RPE65 together with a reduced c-wave amplitude indicate a dysfunctional RPE. The retinal phenotype in Exoc5-/- mice was present at 20 weeks, but was more pronounced at 27 weeks, indicating progressive disease phenotype. We previously showed that the exocyst is necessary for photoreceptor ciliogenesis and retinal development. Here, we report that exoc5 mutant zebrafish and mice with RPE-specific genetic ablation of Exoc5 develop abnormal RPE pigmentation, resulting in retinal cell dystrophy and loss of visual pigments associated with compromised vision. Together, these data suggest that exocyst-mediated signaling in the RPE is required for RPE structure and function, indirectly leading to photoreceptor degeneration.

Keywords: exocyst complex component 5; photoreceptor; retinal pigmented epithelium; visual function.

MeSH terms

  • Animals
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Photoreceptor Cells / metabolism
  • Photoreceptor Cells / pathology*
  • Retinal Degeneration*
  • Retinal Pigment Epithelium / metabolism
  • Retinal Pigment Epithelium / pathology*
  • Vesicular Transport Proteins / physiology*
  • Vision Disorders / metabolism
  • Vision Disorders / pathology*
  • Zebrafish

Substances

  • EXOC5 protein, mouse
  • Vesicular Transport Proteins