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.
Highlights
Given our previous results showing Exoc5 is necessary for ciliogenesis in photoreceptor cells in zebrafish and mice [15], and that cdc42 and exoc5 are necessary for retinal development in zebrafish and interact synergistically [12], here we investigated the role of Exoc5 in retinal pigmented epithelium (RPE) cell structure and function and retinal development using RPE-specific
Detailed histological examination and H&E staining of 3.5 dpf exoc5−/− retinas showed thinning of the retinal pigmented epithelium (RPE) and photoreceptor layers (Figure 1A)
Our results show the pathological consequences of condition Exoc5 protein loss in RPE on retinal cell function
Summary
In developed countries such as the U.S, glaucoma and cataracts are treated relatively so the most common cause of blindness is or soon will be retinal degenerative creativecommons.org/licenses/by/ 4.0/). In epithelia containing numerous motile cilia, cilia have a propulsive function, while primary cilia have a mechano- and chemosensory function [4] It has been known for over 100 years that epithelial cells possess primary cilia; little had been ascribed regarding function, and primary cilia had even been considered to be vestigial [5]. We discovered that the exocyst a highly conserved eight-protein trafficking complex, and its regulators are necessary for cilia formation in kidney and ocular cells [1,4,5,6,7,8,9]. In a series of studies, we elucidated the critical role that the highly conserved eight-protein exocyst trafficking complex plays in retinal and renal ciliogenesis [6,7,8,9,10]
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