Browsing by Author "Zhang, Liyun"

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    Drug screening with zebrafish visual behavior identifies carvedilol as a potential treatment for an autosomal dominant form of retinitis pigmentosa
    (Springer Nature, 2021-06-01) Ganzen, Logan; Ko, Mee Jung; Zhang, Mengrui; Xie, Rui; Chen, Yongkai; Zhang, Liyun; James, Rebecca; Mumm, Jeff; van Rijn, Richard M.; Zhong, Wenxuan; Pang, Chi Pui; Zhang, Mingzhi; Tsujikawa, Motokazu; Leung, Yuk Fai; Biochemistry and Molecular Biology, School of Medicine
    Retinitis Pigmentosa (RP) is a mostly incurable inherited retinal degeneration affecting approximately 1 in 4000 individuals globally. The goal of this work was to identify drugs that can help patients suffering from the disease. To accomplish this, we screened drugs on a zebrafish autosomal dominant RP model. This model expresses a truncated human rhodopsin transgene (Q344X) causing significant rod degeneration by 7 days post-fertilization (dpf). Consequently, the larvae displayed a deficit in visual motor response (VMR) under scotopic condition. The diminished VMR was leveraged to screen an ENZO SCREEN-WELL REDOX library since oxidative stress is postulated to play a role in RP progression. Our screening identified a beta-blocker, carvedilol, that ameliorated the deficient VMR of the RP larvae and increased their rod number. Carvedilol may directly on rods as it affected the adrenergic pathway in the photoreceptor-like human Y79 cell line. Since carvedilol is an FDA-approved drug, our findings suggest that carvedilol can potentially be repurposed to treat autosomal dominant RP patients.
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    Expression profiling of the retina of pde6c, a zebrafish model of retinal degeneration
    (Nature Publishing group, 2017-12-12) Zhang, Liyun; Zhang, Xinlian; Zhang, Gaonan; Pang, Chi Pui; Leung, Yuk Fai; Zhang, Mingzhi; Zhong, Wenxuan; Biochemistry and Molecular Biology, School of Medicine
    Retinal degeneration often affects the whole retina even though the disease-causing gene is specifically expressed in the light-sensitive photoreceptors. The molecular basis of the retinal defect can potentially be determined by gene-expression profiling of the whole retina. In this study, we measured the gene-expression profile of retinas microdissected from a zebrafish pde6cw59 (pde6c) mutant. This retinal-degeneration model not only displays cone degeneration caused by a cone-specific mutation, but also other secondary cellular changes starting from 4 days postfertilization (dpf). To capture the underlying molecular changes, we subjected pde6c and wild-type (WT) retinas at 5 dpf/ 120 h postfertilization (hpf) to RNA sequencing (RNA-Seq) on the Illumina HiSeq 2,000 platform. We also validated the RNA-Seq results by Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR) of seven phototransduction genes. Our analyses indicate that the RNA-Seq dataset was of high quality, and effectively captured the molecular changes in the whole pde6c retina. This dataset will facilitate the characterization of the molecular defects in the pde6c retina at the initial stage of retinal degeneration.
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    Expression profiling of the RPE in zebrafish smarca4 mutant revealed altered signals that potentially affect RPE and retinal differentiation
    (Molecular Vision, 2014-01-06) Zhang, Liyun; Ma, Ping; Collery, Ross; Trowbridge, Sara; Zhang, Mingzhi; Zhong, Wenxuan; Leung, Yuk Fai; Biochemistry and Molecular Biology, School of Medicine
    Purpose: The purpose of this study was to develop a framework for analyzing retinal pigment epithelium (RPE) expression profiles from zebrafish eye mutants. Methods: The fish model we used was SWI/SNF-related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (smarca4), a retinal dystrophic mutant with a previously described retinal phenotype and expression profiles. Histological and Affymetrix GeneChip analyses were conducted to characterize the RPE defects and underlying differential expression, respectively. Results: Histological analysis revealed that smarca4 RPE was formed, but its differentiation was abnormal. In particular, ultrastructural analysis of smarca4 RPE by transmission electron microscopy demonstrated several defects in melanogenesis. The nature of these defects also suggests that the cytoskeletal dynamics, which are tightly linked with melanogenesis, were impaired in smarca4 RPE. To compare the expression profile of normal wild-type (WT) and smarca4 RPE, the gene expression profiles of microdissected retinas and RPE-attached retinas were measured with Affymetrix GeneChip analysis. The RPE expression values were then estimated from these samples by subtracting the retinal expression values from the expression values of the RPE-attached retinas. A factorial analysis was conducted using the expression values of the RPE, retinal, and whole-embryo samples. Specific rules (contrasts) were built using the coefficients of the resulting fitted models to select for three groups of genes: 1) smarca4-regulated RPE genes, 2) smarca4-regulated retinal genes, and 3) smarca4-regulated RPE genes that are not differentially expressed in the retina. Interestingly, the third group consists of 39 genes that are highly related to cytoskeletal dynamics, melanogenesis, and paracrine and intracellular signal transduction. Conclusions: Our analytical framework provides an experimental approach to identify differentially-regulated genes in the retina and the RPE of zebrafish mutants in which both of these tissues are affected by the underlying mutation. Specifically, we have used the method to identify a group of 39 genes that can potentially explain the melanogenesis defect in the smarca4 RPE. In addition, several genes in this group are secreted signaling molecules. Thus, this observation further implicates that the smarca4 RPE might play a role in the retinal dystrophic phenotype in smarca4.
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    The Role of egr1 in Early Zebrafish Retinogenesis
    (Public Library of Science, 2013) Zhang, Liyun; Cho, Jin; Ptak, Devon; Leung, Yuk Fai; Biochemistry and Molecular Biology, School of Medicine
    Proper retinal cell differentiation is essential for establishing a functional retina. The purpose of this study is to investigate the role of early growth response 1 (egr1), a transcription factor (TF) that has been reported to control eye development and function, on retinal differentiation in zebrafish. Specifically, cellular changes in the Egr1-knockdown retinas were characterized by immunohistochemistry at 72 and 120 hours post-fertilization (hpf). The results indicate that Egr1 knockdown specifically suppressed the differentiation of subtypes of amacrine cells (ACs) and horizontal cells (HCs), including Parvalbumin- and GABA-positive ACs as well as Islet1-positive HCs. In addition, the knockdown induced a general delay of development of the other retinal cell types. These differentiation problems, particularly the ones with the ACs and HCs, also compromised the integrity of the inner and outer plexiform layers. In the Egr1-knockdown retinas, the expression of ptf1a, a TF that controls the specification of ACs and HCs, was prolonged and found in ectopic locations in the retina up to 72 hpf. Then, it became restricted to the proliferative marginal zone as in the control retinas at 120 hpf. This abnormal and prolonged expression of ptf1a during retinogenesis might affect the differentiation of ACs and HCs in the Egr1-knockdown retinas.