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Photoreceptor anatomy and retinal architecture. (A) The photoreceptor cell consists of an outer segment (OS), a modified cilium which contains the light-detecting machinery; a connecting cilium (CC) that connects the OS to the rest of the cell; an inner segment (IS) containing densely packed mitochondria; a cell body (CB); and a synaptic body (SB) where downstream neurons innervate the photoreceptor. Microvilli called calyceal processes (CPs) grow from the apical IS and surround the base of the OS. (B) The distinct organisation and cell types in the retina. At the back of the eye are the photoreceptor cells which are supported by the retinal pigment epithelium (RPE). Depicted are the photoreceptor types present within the human retina: rod photoreceptors shown in grey and cone photoreceptors sensitive to blue, green, or red light, depicted in corresponding colours. The photoreceptor cell bodies sit in the outer nuclear layer (ONL). The photoreceptor synapses make connections with the downstream bipolar and horizontal cells in the outer plexiform layer (OPL), and the cell bodies of those interneurons as well as amacrine cells and Müller glia form the inner nuclear layer (INL). The interneurons synapse with the retinal ganglion cells in the inner plexiform layer (IPL), and the retinal ganglion cells form the ganglion cell layer (GCL). The retinal ganglion cell axons form the nerve fibre layer (NFL); the retinal astrocytes sit within this region.
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Photoreceptor dysfunctions and degenerative diseases are significant causes of vision loss in patients, with few effective treatments available. Targeted interventions to prevent or reverse photoreceptor-related vision loss are not possible without a thorough understanding of the underlying mechanism leading to disease, which is exceedingly difficu...
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... are maximally sensitive to specific wavelengths of light and allow for high-acuity daytime/ colour vision; and rod photoreceptors, which are extremely sensitive and can detect single photons, facilitating vision under dim light conditions. Photoreceptors have developed unique morphological features and compartments to allow for light detection ( Fig. 1) (Goldberg et al., 2016;Morshedian and Fain, 2017;Sung and Chuang, 2010). Photoreceptor cells have an outer segment (OS), a modified cilium which, in the case of rods, contains stacked membranous discs densely studded with the photosensitive rhodopsin protein (May-Simera et al., 2017). These membranous discs are encapsulated by the ...
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... cells within the retina are organised in a specific hierarchy, giving rise to discrete cellular and synaptic layers (Fig. 1B). The photoreceptor cell bodies form the outer nuclear layer (ONL). Light information is relayed from the photoreceptor cells to downstream interneurons, and the layer where the photoreceptors synapse with these downstream cells is referred to as the outer plexiform layer (OPL). The interneuron (bipolar, horizontal, and amacrine) and ...
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... zebrafish model of kif3a mutations had photoreceptors with either absent or short, extremely abnormal OSs containing swirls of membrane and few properly stacked discs at 3-4 dpf ( Pooranachandran and Malicki, 2016;Raghupathy et al., 2016). At 5 dpf, cell death was significantly increased in the outer retina and the central retina ONL was thin, with few, degenerating photoreceptors (Raghupathy et al., 2016). ...
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... 15 (PCDH15) is a cell adhesion molecule and component of the tip links that connect adjacent stereocilia of the inner ear and open ion channels in response to deflection; there is evidence that PCDH15 similarly functions in linking the photoreceptor microvilli, CPs (Fig. 1), to the OS exterior ( Schietroma et al., 2017). The function of CPs is unclear, in part because not all species utilised to investigate photoreceptors possess photoreceptor CPs -while humans and zebrafish have CPs, mice do not (Fig. 5). Mutations in PCDH15 result in Usher syndrome (USH), a condition characterised by vision and hearing ...
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... zebrafish mutants had small or absent/-detached photoreceptor OSs at 4 dpf, and the photoreceptors that were present had abnormal disc stacking and growth (Miles et al., 2021); this worsened with age. Additionally, the photoreceptor CP attachments were poor, and CPs were progressively lost (Miles et al., 2021). The mutants also displayed gaps between the inner and outer segments, and abnormal ribbon synapses. ...
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... in PDE6C result in cone dystrophy and achromatopsia (Chang et al., 2009;Thiadens et al., 2009). Zebrafish with pde6c mutations had photoreceptor degeneration and were functionally blind at 7 dpf ( Nishiwaki et al., 2008;Stearns et al., 2007). Interestingly, rod photoreceptors appeared dysmorphic and underwent degeneration post cone loss in Fig. 6. Subretinal lipid deposits in the rp1l1 mutant zebrafish. (A) TEM images showing disorganised photoreceptor outer segments and subretinal deposits (arrowheads) in the rp1l1 mutants. (B) H&E-stained retinas. Mutant retinas have holes behind the photoreceptor outer segments (arrowhead) due to the deposit contents being removed during tissue processing. (C) Cryosectioned retinas stained with oil ...
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... circadian regulator 2 (PER2) is part of the molecular clock that contributes to circadian rhythm establishment. per2 mutants had visual defects and abnormal, unanchored ribbon synapses at 5 dpf (Huang et al., 2018). The mutants also had altered expression of cone-specific genes and synj1. ...
Citations
... Zebrafish have been widely adopted as a model for studying the visual system (Noel et al., 2022). The zebrafish retina exhibits the same layered organization as the human retina, except for the lack of a central fovea, and contains a mix of rods and cones (≈60% cones in adults; Zang and Neuhauss, 2021). ...
... While CPs remain poorly understood, a possible association with the retinal USH1 phenotype brought them to attention as a potentially critical aspect of photoreceptor biology (Sahly et al., 2012;Schietroma et al., 2017;Miles et al., 2021). As zebrafish is a favourable model for photoreceptor disease studies (Noel et al., 2022), our detailed examination of CP characteristics in wild-type zebrafish will provide a useful reference for future investigation. Most notably, we characterized the transition from dynamic tangential processes to vertical CPs just prior to OS formation, as well as how CPs undergo continuous turnover of their actin cores while maintaining constant lengths. ...
Vertebrate photoreceptors detect light through a large cilium-based outer segment, which is filled with photopigment-laden membranous discs. Surrounding the base of the outer segment are microvilli-like calyceal processes (CPs). While CP disruption has been associated with altered outer segment morphology and photoreceptor degeneration, the role of the processes remains elusive. Here, we used zebrafish as a model to characterize CPs. We quantified CP parameters and report a strong disparity in outer segment coverage between photoreceptor subtypes. CP length is stable across light and dark conditions, while heat shock inducible expression of tagged actin revealed rapid turnover of the CP actin core. Detailed imaging of the embryonic retina uncovered substantial remodeling of the developing photoreceptor apical surface, including a transition from dynamic tangential processes to vertically-oriented CPs immediately prior to outer segment formation. Remarkably, we also found a direct connection between apical extensions of the Müller glia and retinal pigment epithelium, arranged as bundles around the ultraviolet sensitive cones. In summary, our data characterize the structure, development, and surrounding environment of photoreceptor microvilli in the zebrafish retina.
... Zebrafish have been widely adopted as a model for studying the visual system [11]. The zebrafish retina exhibits the same layered organization as the human retina, except for the lack of a central fovea, and contains a mix of rods and cones (~60% cones in adults [12]). ...
... While CPs remain poorly understood, a potential association with the retinal USH1 phenotype brought them to attention and highlighted the need for more research [5,8,10]. As zebrafish is a favourable model for photoreceptor disease studies [11], our detailed examination of CP characteristics in wildtype zebrafish will provide a useful reference for future investigation. ...
Vertebrate photoreceptors detect light through a large cilium-based outer segment, which is filled with photopigment-laden membranous disks. Surrounding the base of the outer segment are calyceal processes (CPs), actin-based microvilli-like protrusions extending from the apical surface of the adjacent inner segment. While CP disruption has been associated with altered outer segment morphology and photoreceptor degeneration, the role of the processes remains elusive. Here, we used zebrafish as a model to characterize CPs. We quantified CP length, number, and diameter, and report a strong disparity in outer segment coverage between different photoreceptor subtypes. CP length was stable across light and dark conditions, while heat shock inducible expression of tagged actin revealed rapid turnover of the CP actin core and of the actin roots extending into the inner segment. Detailed imaging of the larval zebrafish retina revealed the presence of dynamic tangential processes extending from the photoreceptor progenitor apical surface up until the emergence of an actin dome over the growing inner segment. As the tangential processes retracted, CPs emerged just prior to outer segment formation. CPs did not accompany the emerging outer segment cilium but immediately aligned with the nascent outer segment discs. Remarkably, we also found a direct connection between apical extensions of the Müller glia and retinal pigment epithelium, arranged as bundles around the CP-encircled outer segments of the ultraviolet sensitive cones. In summary, our data characterizes CP structure, development, and surrounding environment in the zebrafish retina.
... The expression of cytochrome P450 enzymes, which metabolize xenobiotic compounds similarly to those in mammals, makes zebrafish valuable for evaluating drug hepatotoxicity and screening potential hepatoprotective compounds, thereby providing insights into toxicology and drug metabolism [43]. Additionally, zebrafish genetic tractability and cone-rich retinas provide unique opportunities to model various photoreceptor diseases [44], and zebrafish models of ocular coloboma have contributed to our understanding of the optic fissure morphogenesis and associated eye and lens defects [45]. Available ophthalmological tools, such as electroretinography and optical coherence tomography, further enhance the suitability of zebrafish for retinal assessment [44]. ...
... Additionally, zebrafish genetic tractability and cone-rich retinas provide unique opportunities to model various photoreceptor diseases [44], and zebrafish models of ocular coloboma have contributed to our understanding of the optic fissure morphogenesis and associated eye and lens defects [45]. Available ophthalmological tools, such as electroretinography and optical coherence tomography, further enhance the suitability of zebrafish for retinal assessment [44]. Zebrafish can be infected with many pathogenic microorganisms, including bacteria, viruses, Mycoplasma, and chlamydia [46][47][48]. ...
Simple Summary
Zebrafish is a crucial in vivo model for lung cancer research and is widely employed in studies focusing on cancer proliferation, metastasis, and angiogenesis. It plays a pivotal role in cancer drug development, being used for target validation, compound screening, and personalized therapy. This review provides a comprehensive overview of the current state of lung cancer research that uses zebrafish, highlighting the advantages and limitations of this model organism and discussing future directions in the field.
Abstract
Zebrafish is increasingly used as a model organism for cancer research because of its genetic and physiological similarities to humans. Modeling lung cancer (LC) in zebrafish has received significant attention. This review focuses on the insights gained from using zebrafish in LC research. These insights range from investigating the genetic and molecular mechanisms that contribute to the development and progression of LC to identifying potential drug targets, testing the efficacy and toxicity of new therapies, and applying zebrafish for personalized medicine studies. This review provides a comprehensive overview of the current state of LC research performed using zebrafish, highlights the advantages and limitations of this model organism, and discusses future directions in the field.
... Zebrafish retinas exhibit the typical morphology found in vertebrate retinas, resembling adult retinas, and share both anatomical and functional similarities with human retinas [29,34]. While the macula is a cone-shaped, dense region responsible for central high-resolution color vision in the human retina [35], recent discoveries have identified a comparable macular area in the retinas of zebrafish larvae, which plays a crucial role in extremely sensitive vision, akin to the human macula [36,37]. Furthermore, the arrangement of neural networks and gene expression patterns in zebrafish photoreceptors closely resemble those observed in humans [38]. ...
... The ONL consists of one rod type and four morphologically and spectrally distinct cone subtypes, namely short single cones (ultraviolet (UV)-sensitive), long single cones (blue-sensitive), double cone accessory members (green-sensitive), and double cone principle members (red-sensitive) [42,43]. The INL is composed of interneurons (bipolar cells, horizontal cells, and amacrine cells) and Müller glia [36]. The plexus layer lies between the nuclear layers and serves as the primary site of synaptic connections between retinal neurons. ...
... The plexus layer lies between the nuclear layers and serves as the primary site of synaptic connections between retinal neurons. The OPL contains photoreceptors, bipolar cells, and horizontal cells, while the IPL consists of bipolar cells, amacrine cells, and ganglion cells [36]. ...
The presence of contaminants in the environment has increased in recent years, and studies have demonstrated that these contaminants have the ability to penetrate the blood–retinal barrier and directly affect the visual systems of organisms. Zebrafish are recognized as an ideal model for human eye diseases due to their anatomical and functional similarities to the human eye, making them an efficient and versatile organism for studying ocular toxicity caused by environmental contaminants in the field of environmental toxicology. Meanwhile, zebrafish exhibit a diverse repertoire of visually mediated behaviors, and their visual system undergoes complex changes in behavioral responses when exposed to environmental contaminants, enabling rapid assessment of the ocular toxicity induced by such pollutants. Therefore, this review aimed to highlight the effectiveness of zebrafish as a model for examining the effects of environmental contaminants on ocular development. Special attention is given to the visually mediated behavior of zebrafish, which allows for a rapid assessment of ocular toxicity resulting from exposure to environmental contaminants. Additionally, the potential mechanisms by which environmental contaminants may induce ocular toxicity are briefly outlined.
... Both rods and cones PR can be affected by developmental diseases. As reviewed by Noel, Allison, MacDonald, & Hocking (2022) [53], defective cellular processes such as inefficient cell adhesion and impaired vesicle trafficking, along with ciliopathies, can drive PR diseases and degeneration, and can generally be modeled by producing mutants expressing failed visual function and ocular architecture genes. ...
Despite the obvious morphological differences in the visual system, zebrafish share a similar architecture and components of the same embryonic origin as humans. The zebrafish retina has the same layered structure and cell types with similar metabolic and phototransduction support as humans, and is functional 72 h after fertilization, allowing tests of visual function to be performed. The zebrafish genomic database supports genetic mapping studies as well as gene editing, both of which are useful in the ophthalmological field. It is possible to model ocular disorders in zebrafish, as well as inherited retinal diseases or congenital or acquired malformations. Several approaches allow the evaluation of local pathological processes derived from systemic disorders, such as chemical exposure to produce retinal hypoxia or glucose exposure to produce hyperglycemia, mimicking retinopathy of prematurity or diabetic retinopathy, respectively. The pathogenesis of ocular infections, autoimmune diseases, or aging can also be assessed in zebrafish larvae, and the preserved cellular and molecular immune mechanisms can be assessed. Finally, the zebrafish model for the study of the pathologies of the visual system complements certain deficiencies in experimental models of mammals since the regeneration of the zebrafish retina is a valuable tool for the study of degenerative processes and the discovery of new drugs and therapies.
Clinical visual electrophysiology is used to assess visual function and differentiate between acquired and inherited retinal diseases (IRD). This chapter will describe electroretinogram (ERG) and summarize International Society for Clinical Electrophysiology of Vision standards for ERG as well as discuss the uses of ERGs for identifying IRDs. ERG uses electrodes placed on the cornea or skin of the adnexa to measure the retina’s electrical activity in response to light stimulus. This stimulus consists of brief flashes of light presented in a full-field cupola during four dark adapted and two light adapted conditions. ERG measures activity in the inner and outer retinal layers from the rods and cones during the light and dark adopted conditions. There is substantial variability in the phenotypic expression of different genes responsible for IRDs. However, ERGs, in combination with ophthalmic exams and patient history, can aid in identification of numerous IRDs. IRDs can be identified based on whether they affect the rod pathways and evidence abnormalities during dark-adapted ERGs and/or affect the cone pathway and evidence abnormalities during light-adapted ERGs. Abnormalities in the rod pathway are characteristic of retinitis pigmentosa, the most common IRD, and congenital stationary night blindness. ERG’s ability to discern whether the central or peripheral function is affected is useful in identifying diseases that primarily affect central retinal functioning such as cone-rod dystrophies and cone dysfunction syndromes.
Age‐related vision loss caused by retinal neurodegenerative pathologies is becoming more prevalent in our ageing society. To understand the physiological and molecular impact of ageing on retinal homeostasis, we used the short‐lived African turquoise killifish, a model known to naturally develop central nervous system (CNS) ageing hallmarks and vision loss. Bulk and single‐cell RNA‐sequencing (scRNAseq) of three age groups (6‐, 12‐, and 18‐week‐old) identified transcriptional ageing fingerprints in the killifish retina, unveiling pathways also identified in the aged brain, including oxidative stress, gliosis, and inflammageing. These findings were comparable to observations in the ageing mouse retina. Additionally, transcriptional changes in genes related to retinal diseases, such as glaucoma and age‐related macular degeneration, were observed. The cellular heterogeneity in the killifish retina was characterized, confirming the presence of all typical vertebrate retinal cell types. Data integration from age‐matched samples between the bulk and scRNAseq experiments revealed a loss of cellular specificity in gene expression upon ageing, suggesting potential disruption in transcriptional homeostasis. Differential expression analysis within the identified cell types highlighted the role of glial/immune cells as important stress regulators during ageing. Our work emphasizes the value of the fast‐ageing killifish in elucidating molecular signatures in age‐associated retinal disease and vision decline. This study contributes to the understanding of how age‐related changes in molecular pathways may impact CNS health, providing insights that may inform future therapeutic strategies for age‐related pathologies.
The eye is particularly suited to gene therapy due to its accessibility, immunoprivileged state and compartmentalised structure. Indeed, many clinical trials are underway for therapeutic gene strategies for inherited retinal degenerations (IRDs). However, as there are currently 281 genes associated with IRD, there is still a large unmet need for effective therapies for the majority of IRD-causing genes. In humans, RAB28 null and hypomorphic alleles cause autosomal recessive cone-rod dystrophy (arCORD). Previous work demonstrated that restoring wild type zebrafish Rab28 via germline transgenesis, specifically in cone photoreceptors, is sufficient to rescue the defects in outer segment phagocytosis (OSP) observed in zebrafish rab28-/- knockouts (KO). This rescue suggests that gene therapy for RAB28-associated CORD may be successful by RAB28 gene restoration to cones. It also inspired us to critically consider the scenarios in which zebrafish can provide informative preclinical data for development of gene therapies. Thus, this review focuses on RAB28 biology and disease, and delves into both the opportunities and limitations of using zebrafish as a model for both gene therapy development and as a diagnostic tool for patient variants of unknown significance (VUS).
