Knocking out lca5 in zebrafish causes cone-rod dystrophy due to impaired outer segment protein trafficking

Qu, Zhen; Yimer, Tinsae Assefa; Xie, Shanglun; Wong, Fulton; Yu, Shanshan; Gao, Liang; Han, Shanshan; Ma, Juanjuan; Lu, Zhaojing; Hu, Xuebin; Qin, Yayun; Huang, Yu-Wen; Lv, Yuexia; Li, Jingzhen; Tang, Zhaohui; Liu, Fei; Liu, Mugen

doi:10.1016/j.bbadis.2019.07.009

Cited by 21 publications

(15 citation statements)

References 35 publications

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“…The zebrafish has emerged as a very powerful tool for investigating the in vivo developmental toxicity of compounds on a large scale [33][34][35]. The small size, ease of genetic manipulations, and relatively economical cost has paved the way for zebrafish to be the best organism for human disease models [36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53]. The zebrafish developmental toxicity study revealed the chronic toxicity of CM1 and CM2.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic Evaluation and Anti-Angiogenic Effects of Two Furano-Sesquiterpenoids from Commiphora myrrh Resin

et al. 2020

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Commiphora myrrh resin (Myrrh) has been used in traditional Arabic medicine to treat various inflammatory diseases. Two furano-sesquiterpenoids, 2-methoxyfuranodiene (CM1) and 2-acetoxyfuranodiene (CM2), were isolated from the chloroform fraction of the ethanolic extract of Arabic Commiphora myrrh resin. The cytotoxicity of the compounds was evaluated using human liver carcinoma, breast cancer cells (HepG2 and MCF-7, respectively) and normal human umbilical vein endothelial cells (HUVECs) cell lines. The development toxicity and anti-angiogenic activity of both compounds were also evaluated using zebrafish embryos. Cell survival assays demonstrated that both compounds were highly cytotoxic in HepG2 and MCF7 cells, with IC50 values of 3.6 and 4.4 µM, respectively. Both compounds induced apoptosis and caused cell cycle arrest in treated HepG2 cells, which was observed using flow cytometric analysis. The development toxicity in zebrafish embryos showed the chronic toxicity of both compounds. The toxicity was only seen when the embryos remained exposed to the compounds for more than three days. The compound CM2 showed a significant level of anti-angiogenic activity in transgenic zebrafish embryos at sublethal doses. Thus, we demonstrated the cytotoxic properties of both compounds, suggesting that the molecular mechanism of these compounds should be further assessed.

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Section: Discussionmentioning

confidence: 99%

Cytotoxic Evaluation and Anti-Angiogenic Effects of Two Furano-Sesquiterpenoids from Commiphora myrrh Resin

et al. 2020

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“…CEP290 mutant zebrafish displays an intracellular transport delay and a decreased visual perception, which is analogous to human LCA patients [ 131 ]. Similarly, the knockout of LCA5 in zebrafish using CRISPR/Cas9 technology causes the impaired OS protein trafficking and then cone–rod dystrophy, which mimics the phenotype of cone–rod dystrophy in humans [ 132 ].…”

Section: Zebrafish As a Model For Studying Mechanisms Of Eye Disordersmentioning

confidence: 99%

Zebrafish Model in Ophthalmology to Study Disease Mechanism and Drug Discovery

Hong

Luo

2021

Pharmaceuticals

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Visual impairment and blindness are common and seriously affect people’s work and quality of life in the world. Therefore, the effective therapies for eye diseases are of high priority. Zebrafish (Danio rerio) is an alternative vertebrate model as a useful tool for the mechanism elucidation and drug discovery of various eye disorders, such as cataracts, glaucoma, diabetic retinopathy, age-related macular degeneration, photoreceptor degeneration, etc. The genetic and embryonic accessibility of zebrafish in combination with a behavioral assessment of visual function has made it a very popular model in ophthalmology. Zebrafish has also been widely used in ocular drug discovery, such as the screening of new anti-angiogenic compounds or neuroprotective drugs, and the oculotoxicity test. In this review, we summarized the applications of zebrafish as the models of eye disorders to study disease mechanism and investigate novel drug treatments.

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“…Defective ciliary trafficking due to the inability of lebercilin to interact with the IFT machinery results in early onset photoreceptor degeneration in Lca5 mutant mice, mimicking the LCA phenotype (Boldt et al, 2011). In a recent study, lca5 −/− zebrafish photoreceptors presented an abnormal distribution of Ift88, which is in agreement with lebercilin interacting with the IFT machinery (Qu et al, 2019).…”

Section: Leber Congenital Amaurosismentioning

confidence: 78%

On the Wrong Track: Alterations of Ciliary Transport in Inherited Retinal Dystrophies

Sánchez-Bellver

Toulis

Marfany

2021

Front. Cell Dev. Biol.

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Ciliopathies are a group of heterogeneous inherited disorders associated with dysfunction of the cilium, a ubiquitous microtubule-based organelle involved in a broad range of cellular functions. Most ciliopathies are syndromic, since several organs whose cells produce a cilium, such as the retina, cochlea or kidney, are affected by mutations in ciliary-related genes. In the retina, photoreceptor cells present a highly specialized neurosensory cilium, the outer segment, stacked with membranous disks where photoreception and phototransduction occurs. The daily renewal of the more distal disks is a unique characteristic of photoreceptor outer segments, resulting in an elevated protein demand. All components necessary for outer segment formation, maintenance and function have to be transported from the photoreceptor inner segment, where synthesis occurs, to the cilium. Therefore, efficient transport of selected proteins is critical for photoreceptor ciliogenesis and function, and any alteration in either cargo delivery to the cilium or intraciliary trafficking compromises photoreceptor survival and leads to retinal degeneration. To date, mutations in more than 100 ciliary genes have been associated with retinal dystrophies, accounting for almost 25% of these inherited rare diseases. Interestingly, not all mutations in ciliary genes that cause retinal degeneration are also involved in pleiotropic pathologies in other ciliated organs. Depending on the mutation, the same gene can cause syndromic or non-syndromic retinopathies, thus emphasizing the highly refined specialization of the photoreceptor neurosensory cilia, and raising the possibility of photoreceptor-specific molecular mechanisms underlying common ciliary functions such as ciliary transport. In this review, we will focus on ciliary transport in photoreceptor cells and discuss the molecular complexity underpinning retinal ciliopathies, with a special emphasis on ciliary genes that, when mutated, cause either syndromic or non-syndromic retinal ciliopathies.

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Knocking out lca5 in zebrafish causes cone-rod dystrophy due to impaired outer segment protein trafficking

Cited by 21 publications

References 35 publications

Cytotoxic Evaluation and Anti-Angiogenic Effects of Two Furano-Sesquiterpenoids from Commiphora myrrh Resin

Cytotoxic Evaluation and Anti-Angiogenic Effects of Two Furano-Sesquiterpenoids from Commiphora myrrh Resin

Zebrafish Model in Ophthalmology to Study Disease Mechanism and Drug Discovery

On the Wrong Track: Alterations of Ciliary Transport in Inherited Retinal Dystrophies

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