Conditional loss of the exocyst component exoc5 in retinal pigment epithelium (Rpe) results in rpe dysfunction, photoreceptor cell degeneration, and decreased visual function

Bärbel Rohrer, Manas R. Biswal, Elisabeth Obert, Yujing Dang, Yanhui Su, Xiaofeng Zuo, Ben Fogelgren, Altaf A. Kondkar, Glenn P. Lobo, Joshua H. Lipschutz

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number5083
JournalInternational journal of molecular sciences
Volume22
Issue number10
DOIs
StatePublished - May 11 2021

Bibliographical note

Funding Information:
Funding: This work was supported in part by grants from the NIH/NEI (R21EY025034 and R01EY030889 to G.P.L., R01EY019320 to B.R., P30DK074038 to J.H.L.), VA (Merit Award I01 BX000820 to J.H.L.; RX000444 and BX003050 to B.R.), American Heart Association AWRP Winter 2017 Collaborative Sciences Award (J.H.L.), and Dialysis Clinic, Inc. (DCI) award to G.P.L. and J.H.L. NIH/NEI award EY027013-02 and USF Taneja College of Pharmacy startup grant to M.R.B.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Exocyst complex component 5
  • Photoreceptor
  • Retinal pigmented epithelium
  • Visual function

PubMed: MeSH publication types

  • Journal Article

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