Zebrafish have been widely used as a model system for studying developmental processes, but in the last decade, they have also emerged as a valuable system for modeling human disease. The development and function of zebrafish organs are strikingly similar to those of humans, and the ease of creating mutant or transgenic fish has facilitated the generation of disease models. Here, we highlight the use of zebrafish for defining disease pathways and for discovering new therapies.

https://dm5migu4zj3pb.cloudfront.net/manuscripts/60000/60434/JCI60434.v1.pdf

Hooked! Modeling human disease in zebrafish

Müller glia: Stem cells for generation and regeneration of retinal neurons in teleost fish.

The steady increase in the incidence of obesity among adults has been paralleled with higher levels of obesity-associated breast cancer. While recent studies have suggested that adipose stromal/stem cells (ASCs) isolated from obese women enhance tumorigenicity, the mechanism(s) by which this occurs remains undefined. Evidence suggests that increased adiposity results in increased leptin secretion from adipose tissue, which has been shown to increased cancer cell proliferation. Previously, our group demonstrated that ASCs isolated from obese women (obASCs) also express higher levels of leptin relative to ASCs isolated from lean women (lnASCs) and that this obASC-derived leptin may account for enhanced breast cancer cell growth. The current study investigates the impact of inhibiting leptin expression in lnASCs and obASCs on breast cancer cell (BCC) growth and progression. Estrogen receptor positive (ER+) BCCs were co-cultured with leptin shRNA lnASCs or leptin shRNA obASCs and changes in the proliferation, migration, invasion, and gene expression of BCCs were investigated. To assess the direct impact of leptin inhibition in obASCs on BCC proliferation, MCF7 cells were injected alone or mixed with control shRNA obASCs or leptin shRNA obASCs into SCID/beige mice. ER+ BCCs were responsive to obASCs during direct co-culture, whereas lnASCs were unable to increase ER+ BCC growth. shRNA silencing of leptin in obASCs negated the enhanced proliferative effects of obASC on BCCs following direct co-culture. BCCs co-cultured with obASCs demonstrated enhanced expression of epithelial-to-mesenchymal transition (EMT) and metastasis genes (SERPINE1, MMP-2, and IL-6), while BCCs co-cultured with leptin shRNA obASCs did not display similar levels of gene induction. Knockdown of leptin significantly reduced tumor volume and decreased the number of metastatic lesions to the lung and liver. These results correlated with reduced expression of both SERPINE1 and MMP-2 in tumors formed with MCF7 cells mixed with leptin shRNA obASCs, when compared to tumors formed with MCF7 cells mixed with control shRNA obASCs. This study provides mechanistic insight as to how obesity enhances the proliferation and metastasis of breast cancer cells; specifically, obASC-derived leptin contributes to the aggressiveness of breast cancer in obese women.

https://link.springer.com/content/pdf/10.1186%2Fs13058-015-0622-z.pdf

Leptin produced by obese adipose stromal/stem cells enhances proliferation and metastasis of estrogen receptor positive breast cancers.

Millions of people are affected by visual impairment and blindness globally, and the prevalence of vision loss is likely to increase as we are living longer. However, many ocular diseases remain poorly controlled due to lack of proper understanding of the pathogenesis and the corresponding lack of effective therapies. Consequently, there is a major need for animal models that closely mirror the human eye pathology and at the same time allow higher-throughput drug screening approaches. In this context, zebrafish as an animal model organism not only address these needs but can in many respects reflect the human situation better than the current rodent models. Over the past decade, zebrafish have become an established model to study a variety of human diseases and are more recently becoming a valuable tool for the study of human ophthalmological disorders. Many human ocular diseases such as cataract, glaucoma, diabetic retinopathy, and age-related macular degeneration have already been modelled in zebrafish. In addition, zebrafish have become an attractive model for pre-clinical drug toxicity testing and are now increasingly used by scientists worldwide for the discovery of novel treatment approaches. This review presents the advantages and uses of zebrafish for ophthalmological research.

/pdf/zebrafish-on-the-move-towards-ophthalmological-research-28gp0uhex2.pdf

Zebrafish—on the move towards ophthalmological research

We have developed a multi-channel microfluidic perfusion platform for culturing zebrafish embryos and capturing live images of various tissues and organs inside the embryo. The Fish and Chips was micro-fabricated in silicon and glass for reproducibility and accuracy of the microfluidic structure. The microfluidic platform consists of three parts: a microfluidic gradient generator, a row of eight fish tanks, in which the fish embryos are individually placed, and eight output channels. The fluidic gradient generator supports dose-dependent drug and chemical studies. A unique perfusion system ensures a uniform and constant flow of media to the fish tank while the wastes are efficiently removed. The fish tanks restrict the embryo movements, except rotationally, for live imaging of internal tissues and organs. The embryos showed developmental abnormalities under the influence of the drug valproic acid (VPA).

Fish and Chips: a microfluidic perfusion platform for monitoring zebrafish development

Background
The roles of the Hedgehog (Hh) pathway in controlling vertebrate retinal development have been studied extensively; however, species- and context-dependent findings have provided differing conclusions. Hh signaling has been shown to control both population size and cell cycle kinetics of proliferating retinal progenitors, and to modulate differentiation within the retina by regulating the timing of cell cycle exit. While cell cycle exit has in turn been shown to control cell fate decisions within the retina, a direct role for the Hh pathway in retinal cell fate decisions has yet to be established in vivo.

https://link.springer.com/content/pdf/10.1186%2F1471-213X-9-52.pdf

Expanded progenitor populations, vitreo-retinal abnormalities, and Müller glial reactivity in the zebrafish leprechaun/patched2 retina

The Hedgehog (Hh) pathway is well known to control proliferation, differentiation, and patterning throughout the developing vertebrate central nervous system.1–4 In the vertebrate retina, Hh activity plays an integral role in the coordination of tissue growth and patterning through its influence on cell cycle progression of proliferating neuroblasts, which influences the timing of cell cycle exit and differentiation.5,6 Indeed, the mitogenic effects of the Hh pathway on retinal progenitors during development have been demonstrated in multiple model organisms.7 In zebrafish and Xenopus embryos, Hh pathway activation positively regulates cell cycle progression by influencing the lengths of the G1 and G2 phases of the cell cycle.6 Consistent with these findings, Shh is essential for the maintenance of retinal progenitor proliferation in mice.8,9

The Hh receptor Patched is a tumor suppressor and negative regulator of the Hh pathway.10,11 Mutations in the human PTCH gene have been linked to BCNS (OMIM 109400; Online Mendelian Inheritance in Man http://www.ncbi.nlm.nih.gov/Omim; National Center for Biotechnology Information, Bethesda, MD), a disorder characterized by dental and skeletal defects, as well as a predisposition to early- and late-onset tumorigenesis (reviewed in Ref. 12). Early lethality in Ptch1−/− mice,13 an established model for BCNS,13,14 has limited the investigation of the effects of loss of Patched function to largely developmental contexts. Interestingly, postnatal Ptch1+/− mice possess retinal dysplasias and epiretinal membranes—structural abnormalities that arise at the vitreoretinal interface. Dysplastic regions of the retina in Ptch1+/− mice are characterized by foci of disrupted lamination and the presence of photoreceptor rosettes in the inner nuclear layer (INL).14 Ectopic proliferation of retinal cells is thought to account for retinal dysplasias in Ptch1+/− mice; however, this relationship has not yet been experimentally demonstrated.

In addition to retinal dysplasia and vitreoretinal abnormalities, postnatal Ptch1+/− mice also possess increased proliferation in the retinal margin.15 In lower vertebrates, such as fish, frogs, and chicks, a population of proliferative cells at the retinal margin called the CMZ continues to contribute to the growth of the retina throughout the life of the animal.16,17 The spatial pattern of cells within the CMZ—retinal stem cells in the most peripheral region, followed by proliferative retinal progenitors, and finally differentiating progenitors more centrally—is thought to replicate the temporal sequence of early retinal development.17,18 Loss of a single allele of the mouse Ptch1 gene curiously results in the persistence of a population of retinal progenitors very reminiscent of the CMZ, a structure normally absent in mammals.15

The zebrafish ptc2tj222 (the orthologue of the mammalian Ptch119) mutant was isolated in a genetic screening designed to identify genes involved in the regulation of proliferation during embryonic development.20 The ptc2tj222 mutant possesses a nonsense mutation in the exon encoding the sixth transmembrane domain of Patched 2 that is predicted to abolish its function.20,21 Loss of Patched function results in an overactive Hh pathway, due to derepression of Smoothened, a transmembrane protein responsible for transducing the Hh signal.22,23

Our previous characterization of embryonic retinal development in ptc2 mutants revealed vitreoretinal abnormalities, similar to those observed in Ptch1+/− mice and in human BCNS patients. Our findings suggest that the vitreoretinal abnormalities are developmental in origin.24 Other aspects of retinal development, such as retinal lamination, were normal up to the late embryonic stages (5 days after fertilization [dpf]); however, an increase in the number of proliferative progenitors at the CMZ was observed, suggesting a role during embryonic eye development for Patched2 in negatively regulating the size of this retinal progenitor/stem cell population.24

A small percentage of zebrafish ptc2−/− mutants survive to juvenile stages.20 Given that retinal dysplasias do not appear in Ptch1+/− mice until postnatal stages and the cellular underpinnings of this phenotype is not known, we used juvenile ptc2−/− mutants to gain further insight into the consequences of loss of Patched function on the growth and patterning of the postembryonic retina. Our analyses identified peripheral retinal dysplasias in juvenile ptc2−/− mutants that included disrupted lamination, the presence of ectopic clusters of cells in the INL, and morphologic abnormalities at the retinal margin. Analysis of cell proliferation in the ptc2−/− juvenile retina revealed overproliferation in all retinal regions where proliferative progenitors normally reside (i.e., the CMZ, INL, and outer nuclear layer [ONL]). Continually proliferative progenitors were detected in ptc2−/− mutants adjacent to the CMZ, and proliferative cells were associated locally with dysplastic retinal regions that contained ectopic neurons. Of note, BrdU incorporation assays, combined with immunohistochemistry for retinal neuronal markers, demonstrated that ectopic retinal neurons within these dysplastic regions originated from an ectopic proliferative event. Taken together, our findings support a role for Patched2 in negatively regulating proliferation in the postembryonic retina and demonstrate that ectopic proliferation in the ptc2−/− juvenile retina directly contributes to retinal dysplasias in these mutants.

/pdf/ectopic-proliferation-contributes-to-retinal-dysplasia-in-51b086jaem.pdf

Ectopic proliferation contributes to retinal dysplasia in the juvenile zebrafish patched2 mutant eye

Visual impairment and blindness is widespread across the human population, and the development of therapies for ocular pathologies is of high priority. The zebrafish represents a valuable model organism for studying human ocular disease; it is utilized in eye research to understand underlying developmental processes, to identify potential causative genes for human disorders, and to develop therapies. Zebrafish eyes are similar in morphology, physiology, gene expression, and function to human eyes. Furthermore, zebrafish are highly amenable to laboratory research. This review outlines the use of zebrafish as a model for human ocular diseases such as colobomas, glaucoma, cataracts, photoreceptor degeneration, as well as dystrophies of the cornea and retinal pigmented epithelium.

/pdf/toward-a-better-understanding-of-human-eye-disease-insights-7ju0chmxbh.pdf

Toward a better understanding of human eye disease insights from the zebrafish, Danio rerio.

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Expanded progenitor populations, vitreo-retinal abnormalities, and Müller glial reactivity in the zebrafish leprechaun/patched2 retina

Ectopic proliferation contributes to retinal dysplasia in the juvenile zebrafish patched2 mutant eye

Toward a better understanding of human eye disease insights from the zebrafish, Danio rerio.