The Primary Cilium as a Therapeutic Target in Ocular Diseases

Zhou, Peng; Zhou, Jun

doi:10.3389/fphar.2020.00977

Cited by 14 publications

(9 citation statements)

References 64 publications

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“…The basement membrane is closely connected to the basal folds by half desmosomes located in the innermost layer of Bruch’s membrane. The inside of RPE cells harbors microvillous structures extending between photoreceptor outer segments (POS), which participate in the phagocytic function of the RPE ( Song and Zhou, 2020 ; Zhou and Zhou, 2020 ; Yang et al, 2021 ). The tight junction formed between the single-layer RPE and the gap junction control the movement of substances and at the same time forms the choroid-blood-retinal barrier with Bruch’s membrane and choroid at the lateral retina ( Xie et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Functions and Diseases of the Retinal Pigment Epithelium

2021

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The retinal pigment epithelium is a fundamental component of the retina that plays essential roles in visual functions. Damage to the structure and function of the retinal pigment epithelium leads to a variety of retinopathies, and there is currently no curative therapy for these disorders. Therefore, studying the relationship between the development, function, and pathobiology of the retinal pigment epithelium is important for the prevention and treatment of retinopathies. Here we review the function of the retinal pigment epithelium and its relevance to the pathobiology, and discuss potential strategies for the treatment of retinopathies. In doing so, we provide new viewpoints outlining new ideas for the future study and treatment of retinopathies.

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Section: Introductionmentioning

confidence: 99%

Functions and Diseases of the Retinal Pigment Epithelium

2021

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“…The outer segment of the photoreceptors is a highly modified primary cilium which has evolved to play a crucial role in vision [ 42 ]. Changes in primary cilium morphology or structure have been associated with retinal diseases such as macular diseases, retinitis pigmentosa, Leber congenital amaurosis, cone dystrophies, and other photoreceptor diseases [ 43 , 44 ]. In addition to the CPLANE genes, our search uncovered a number of additional ciliopathy genes associated with multi-systemic, brain, kidney, and eye ciliopathies ( Cep135 , Innp5e , Pex6 , Togaram1 , see Additional file 1 : Table S3).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide screening reveals the genetic basis of mammalian embryonic eye development

Chee

Lanoue²,

Clary³

et al. 2023

BMC Biol

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Background Microphthalmia, anophthalmia, and coloboma (MAC) spectrum disease encompasses a group of eye malformations which play a role in childhood visual impairment. Although the predominant cause of eye malformations is known to be heritable in nature, with 80% of cases displaying loss-of-function mutations in the ocular developmental genes OTX2 or SOX2, the genetic abnormalities underlying the remaining cases of MAC are incompletely understood. This study intended to identify the novel genes and pathways required for early eye development. Additionally, pathways involved in eye formation during embryogenesis are also incompletely understood. This study aims to identify the novel genes and pathways required for early eye development through systematic forward screening of the mammalian genome. Results Query of the International Mouse Phenotyping Consortium (IMPC) database (data release 17.0, August 01, 2022) identified 74 unique knockout lines (genes) with genetically associated eye defects in mouse embryos. The vast majority of eye abnormalities were small or absent eyes, findings most relevant to MAC spectrum disease in humans. A literature search showed that 27 of the 74 lines had previously published knockout mouse models, of which only 15 had ocular defects identified in the original publications. These 12 previously published gene knockouts with no reported ocular abnormalities and the 47 unpublished knockouts with ocular abnormalities identified by the IMPC represent 59 genes not previously associated with early eye development in mice. Of these 59, we identified 19 genes with a reported human eye phenotype. Overall, mining of the IMPC data yielded 40 previously unimplicated genes linked to mammalian eye development. Bioinformatic analysis showed that several of the IMPC genes colocalized to several protein anabolic and pluripotency pathways in early eye development. Of note, our analysis suggests that the serine-glycine pathway producing glycine, a mitochondrial one-carbon donator to folate one-carbon metabolism (FOCM), is essential for eye formation. Conclusions Using genome-wide phenotype screening of single-gene knockout mouse lines, STRING analysis, and bioinformatic methods, this study identified genes heretofore unassociated with MAC phenotypes providing models to research novel molecular and cellular mechanisms involved in eye development. These findings have the potential to hasten the diagnosis and treatment of this congenital blinding disease.

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“…When the IOP is elevated, primary cilia shorten, promoting the expression of tumor necrosis factor α and transforming growth factor β (TGF-β), perhaps initiating mechanisms leading to glaucoma. 171 Some investigations have suggested a direct link between Wnt signaling and glaucoma, since Wnt signaling is involved in the regeneration of the optic nerve after injury and also in IOP regulation. 135,172,173 Recent studies have shown that one of the first genes linked to glaucoma, MYOC producing myocilin, is present in the base of primary cilia and its expression affects pathways related to ciliary signaling, such as TGF-β.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association meta-analysis identifies novel ancestry-specific primary open-angle glaucoma loci and shared biology with vascular mechanisms and cell proliferation

Faro

Bhattacharya

Zhou

et al. 2021

Preprint

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Primary open-angle glaucoma (POAG) is a complex eye disease characterized by progressive loss of optic nerve function that, if untreated, ultimately leads to irreversible blindness. To date, the biological mechanisms causing POAG are still unclear. There is disparity in POAG prevalence, clinical presentations and outcomes across ancestries. Here, we aim to identify unique genetics that underlie risk to POAG and evaluate the potential connection with vascular mechanisms. We performed POAG meta-analysis across 15 biobanks that are part of the Global Biobank Meta-analysis Initiative, with two previously published multi-ancestry analyses for a total of 1,478,037 individuals from six ancestries (46,325 cases and 1,431,712 controls). A total of 109 genome-wide significantly associated loci (p<5e-8) were identified, 18 of which were novel. Three of these novel loci are ancestry-specific, two African-specific and the third specific to northern Europeans. We also identified five sex-specific novel loci, four of which are African-specific and one European-specific. To explore biological implications underlying these variant-trait associations, we performed gene enrichment analysis, gene prioritization analysis and transcriptome-wide association studies (TWAS) implicating genes related to vascular-related functions, blood vessels, angiogenesis, and cancer. A fifth of TWAS-prioritized genes with vascular-related and/or cell senescence/proliferation functional roles or have been implicated in vascular or neoplastic diseases are primary ciliary related genes. We further performed extensive statistical validation analysis of genes in the SIX6 and well-known CDKN2B-AS1 loci, previously implicated in POAG, cardiovascular diseases, and cancers across multiple ancestries. We found evidence of significant interaction between SIX6 rs33912345 and causal variants in chr9p21.3, with concomitant effect on expression of a primary cilia gene CDKN2A and CDKN2B at the CDKN2B-AS1 locus. Phenome-wide association analysis of POAG genetic risk burden across five biobanks and genetic correlation analysis also show the shared biology between POAG and vascular and neoplastic traits. In summary, our findings suggest that some POAG risk variants may be ancestry-specific, sex-specific, or both. Our findings further support the contribution of vascular and proliferation genes in POAG and suggest potential involvement of primary cilia in POAG pathogenesis.

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The Primary Cilium as a Therapeutic Target in Ocular Diseases

Cited by 14 publications

References 64 publications

Functions and Diseases of the Retinal Pigment Epithelium

Functions and Diseases of the Retinal Pigment Epithelium

Genome-wide screening reveals the genetic basis of mammalian embryonic eye development

Genome-wide association meta-analysis identifies novel ancestry-specific primary open-angle glaucoma loci and shared biology with vascular mechanisms and cell proliferation

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