Review

Authors: Nicholas E Baker, Ke Li, Manon Quiquand...

The eye has been one of the most intensively studied organs in Drosophila. The wealth of knowledge about its development, as well as the reagents that have been developed, and the fact that the eye is dispensable for survival, also make the eye suitable for genetic interaction studies and genetic screens. This article provides a brief overview of the methods developed to image and probe eye development at multiple developmental stages, including live imaging, immunostaining of fixed tissues, in situ hybridizations, and scanning electron microscopy and color photography of adult eyes. Also summarized are genetic approaches that can be performed in the eye, including mosaic analysis and conditional mutation, gene misexpression and knockdown, and forward genetic and modifier screens.

Topics: Animals; Developmental Biology; Drosophila; Eye; Gene Expression Regulation, Developmental; Humans; In Situ Hybridization; Microscopy, Electron, Scanning; Mutation

PubMed: 24784530
DOI: 10.1016/j.ymeth.2014.04.007

Review

Authors: Xiangtian Zhou, Machelle T Pardue, P Michael Iuvone...

In the face of an "epidemic" increase in myopia over the last decades and myopia prevalence predicted to reach 2.5 billion people by the end of this decade, there is an urgent need to develop effective and safe therapeutic interventions to slow down this "myopia booming" and prevent myopia-related complications and vision loss. Dopamine (DA) is an important neurotransmitter in the retina and mediates diverse functions including retina development, visual signaling, and refractive development. Inspired by the convergence of epidemiological and animal studies in support of the inverse relationship between outdoor activity and risk of developing myopia and by the close biological relationship between light exposure and dopamine release/signaling, we felt it is timely and important to critically review the role of DA in myopia development. This review will revisit several key points of evidence for and against DA mediating light control of myopia: 1) the causal role of extracellular retinal DA levels, 2) the mechanism and action of dopamine D1 and D2 receptors and 3) the roles of cellular/circuit retinal pathways. We examine the experiments that show causation by altering DA, DA receptors and visual pathways using pharmacological, transgenic, or visual environment approaches. Furthermore, we critically evaluate the safety issues of a DA-based treatment strategy and some approaches to address these issues. The review identifies the key questions and challenges in translating basic knowledge on DA signaling and myopia from animal studies into effective pharmacological treatments for myopia in children.

Topics: Dopamine; Dopamine Agonists; Dopamine Antagonists; Eye; Humans; Myopia; Receptors, Dopamine; Retina; Signal Transduction

PubMed: 28602573
DOI: 10.1016/j.preteyeres.2017.06.003

Review

Authors: Gerard A Lutty, D Scott McLeod

The development of the ocular vasculatures is perfectly synchronized to provide the nutritional and oxygen requirements of the forming human eye. The fetal vasculature of vitreous, which includes the hyaloid vasculature, vasa hyaloidea propria, and tunica vasculosa lentis, initially develops around 4-6 weeks gestation (WG) by hemo-vasculogenesis (development of blood and blood vessels from a common progenitor, the hemangioblast). This transient fetal vasculature expands around 12 WG by angiogenesis (budding from primordial vessels) and remains until a retinal vasculature begins to form. The fetal vasculature then regresses by apoptosis with the assistance of macrophages/hyalocytes. The human choroidal vasculature also forms by a similar process and will supply nutrients and oxygen to outer retina. This lobular vasculature develops in a dense collagenous tissue juxtaposed with a cell constitutively producing vascular endothelial growth factor (VEGF), the retinal pigment epithelium. This epithelial/endothelial relationship is critical in maintaining the function of this vasculature throughout life and maintaining it's fenestrated state. The lobular capillary system (choriocapillaris) develops first by hemo-vasculogenesis and then the intermediate choroidal blood vessels form by angiogenesis, budding from the choriocapillaris. The human retinal vasculature is the last to develop. It develops by vasculogenesis, assembly of CXCR4/CD39 angioblasts or vascular progenitors perhaps using Muller cell Notch1 or axonal neuropilinin-1 for guidance of semaphorin 3A-expressing angioblasts. The fovea never develops a retinal vasculature, which is probably due to the foveal avascular zone area of retina expressing high levels of antiangiogenic factors. From these studies, it is apparent that development of the mouse ocular vasculatures is not representative of the development of the human fetal, choroidal and retinal vasculatures.

Topics: Choroid; Humans; Neovascularization, Pathologic; Retina; Retinal Pigment Epithelium; Retinal Vessels; Vascular Endothelial Growth Factor A; Vitreous Body

PubMed: 29081352
DOI: 10.1016/j.preteyeres.2017.10.001

Authors: Hannah Flach, Julia Krieg, Meike Hoffmeister...

BACKGROUND

The nitric oxide synthase interacting protein (Nosip) has been associated with diverse human diseases including psychological disorders. In line, early neurogenesis of mouse and Xenopus is impaired upon Nosip deficiency. Nosip knockout mice show craniofacial defects and the down-regulation of Nosip in the mouse and Xenopus leads to microcephaly. Until now, the exact underlying molecular mechanisms of these malformations were still unknown.

RESULTS

Here, we show that nosip is expressed in the developing ocular system as well as the anterior neural crest cells of Xenopus laevis. Furthermore, Nosip inhibition causes severe defects in eye formation in the mouse and Xenopus. Retinal lamination as well as dorso-ventral patterning of the retina were affected in Nosip-depleted Xenopus embryos. Marker gene analysis using rax, pax6 and otx2 reveals an interference with the eye field induction and differentiation. A closer look on Nosip-deficient Xenopus embryos furthermore reveals disrupted cranial cartilage structures and an inhibition of anterior neural crest cell induction and migration shown by twist, snai2, and egr2. Moreover, foxc1 as downstream factor of retinoic acid signalling is affected upon Nosip deficiency.

CONCLUSIONS

Nosip is a crucial factor for the development of anterior neural tissue such the eyes and neural crest cells. Developmental Dynamics 247:1070-1082, 2018. © 2018 Wiley Periodicals, Inc.

Topics: Animals; Cartilage; Embryo, Nonmammalian; Embryonic Development; Eye; Gene Knockdown Techniques; Mice; Neural Crest; Neurogenesis; Skull; Ubiquitin-Protein Ligases; Xenopus Proteins; Xenopus laevis

PubMed: 30055071
DOI: 10.1002/dvdy.24659

Review

Authors: Elena Vecino, Arantxa Acera

Programmed cell death (PCD) is a major mechanism for patterning of a variety of complex structures. Cells are initially organized into fairly loose patterns; then, selective death removes the cells between pattern elements to create the correct structures, as a sculptor removes some material to reveal the hidden image. The life or death of a cell is mostly affected by extracellular signals because the intracellular machinery responsible for PCD is constitutively expressed in most animal cells. The optic vesicle originates during gastrulation when the endoderm and mesoderm interact with the adjacent prospective head ectoderm to create a lens. To be formed correctly, the lens must have a precise spatial relationship with the retina. Ganglion cells are the first neurons to be differentiated in the retina. Vertical networks in the inner and outer retina are later interconnected when bipolar cells are formed and connections with ganglion cells are established. This sequential pattern of retinal circuit development is common across vertebrate species. During development of the retina, far more neurons are generated than are ultimately needed with almost one half of them undergoing PCD shortly before establishing meaningful contacts within their targets. However, apoptosis in other eye tissues is not a key event but rather a refinement. Thus, for the final development of the cornea, the control of keratocyte proliferation is more important than cell death events. The molecular mechanisms underlying apoptotic cell death have been conserved throughout evolution; however further investigations are needed to understand the key mechanisms of PCD in different tissues during development.

Topics: Animals; Apoptosis; Cell Proliferation; Cornea; Gastrulation; Gene Expression Regulation, Developmental; Lens, Crystalline; Mammals; Retina

PubMed: 26374527
DOI: 10.1387/ijdb.150070ev

Authors: Jos J Rozema, Arezoo Farzanfar

PURPOSE

During refractive development, eye growth is controlled by a combination of genetically pre-programmed processes and retinal feedback to minimise the refractive error. This work presents a basic differential model of how this process may take place.

METHODS

The description starts from two bi-exponential descriptions of the axial power P (or dioptric distance) and total refractive power P, the difference between which corresponds with the spherical refractive error S. This description is rewritten as an ordinary differential equation and supplemented by a retinal feedback function that combines retinal blur (closed loop) with a term describing excessive axial growth (open loop). This model is controlled by a total of 18 parameters that allow for a wide variety of developmental behaviours.

RESULTS

The proposed model reproduces refractive development growth curves found in the literature for both healthy and myopic eyes. An early onset of myopisation, a large growth term and a high minimum for the crystalline lens power all lead to higher degrees of myopia. Assigning more importance to the feedback than to the pre-programmed growth makes the model more sensitive to myopogenic influences. Applying refractive corrections to the model, undercorrection is found to produce more myopia. The model compensates for a low-powered imposed lens and can return to (near) emmetropia if that imposed lens is removed quickly thereafter. Finally, simulating the effect of a diffuser leads to high myopia.

CONCLUSION

Using a series of basic assumptions, the proposed model recreates many well-known experimental and clinical results about refractive development from the literature while placing them in a standardised context. This contributes to a broader understanding of the origins of refractive errors, and future versions may help in the development of solutions for myopia control.

Topics: Humans; Myopia; Refraction, Ocular; Eye; Models, Biological; Child; Adolescent

PubMed: 39503256
DOI: 10.1111/opo.13412

Review

Authors: Ranjay Chakraborty, Lisa A Ostrin, Debora L Nickla...

PURPOSE

Despite extensive research, mechanisms regulating postnatal eye growth and those responsible for ametropias are poorly understood. With the marked recent increases in myopia prevalence, robust and biologically-based clinical therapies to normalize refractive development in childhood are needed. Here, we review classic and contemporary literature about how circadian biology might provide clues to develop a framework to improve the understanding of myopia etiology, and possibly lead to rational approaches to ameliorate refractive errors developing in children.

RECENT FINDINGS

Increasing evidence implicates diurnal and circadian rhythms in eye growth and refractive error development. In both humans and animals, ocular length and other anatomical and physiological features of the eye undergo diurnal oscillations. Systemically, such rhythms are primarily generated by the 'master clock' in the surpachiasmatic nucleus, which receives input from the intrinsically photosensitive retinal ganglion cells (ipRGCs) through the activation of the photopigment melanopsin. The retina also has an endogenous circadian clock. In laboratory animals developing experimental myopia, oscillations of ocular parameters are perturbed. Retinal signaling is now believed to influence refractive development; dopamine, an important neurotransmitter found in the retina, not only entrains intrinsic retinal rhythms to the light:dark cycle, but it also modulates refractive development. Circadian clocks comprise a transcription/translation feedback control mechanism utilizing so-called clock genes that have now been associated with experimental ametropias. Contemporary clinical research is also reviving ideas first proposed in the nineteenth century that light exposures might impact refraction in children. As a result, properties of ambient lighting are being investigated in refractive development. In other areas of medical science, circadian dysregulation is now thought to impact many non-ocular disorders, likely because the patterns of modern artificial lighting exert adverse physiological effects on circadian pacemakers. How, or if, such modern light exposures and circadian dysregulation contribute to refractive development is not known.

SUMMARY

The premise of this review is that circadian biology could be a productive area worthy of increased investigation, which might lead to the improved understanding of refractive development and improved therapeutic interventions.

Topics: Circadian Rhythm; Disease Progression; Eye; Humans; Myopia; Refraction, Ocular

PubMed: 29691928
DOI: 10.1111/opo.12453

Review

Authors: Jaya Krishnan, Nicolas Rohner

Animals have colonized the entire world from rather moderate to the harshest environments, some of these so extreme that only few animals are able to survive. Cave environments present such a challenge and obligate cave animals have adapted to perpetual darkness by evolving a multitude of traits. The most common and most studied cave characteristics are the regression of eyes and the overall reduction in pigmentation. Studying these traits can provide important insights into how evolutionary forces drive convergent and regressive adaptation. The blind Mexican cavefish (Astyanax mexicanus) has emerged as a useful model to study cave evolution owing to the availability of genetic and genomic resources, and the amenability of embryonic development as the different populations remain fertile with each other. In this review, we give an overview of our current knowledge underlying the process of regressive and convergent evolution using eye degeneration in cavefish as an example.This article is part of the themed issue 'Evo-devo in the genomics era, and the origins of morphological diversity'.

Topics: Animals; Biological Evolution; Caves; Characidae; Eye; Phenotype

PubMed: 27994128
DOI: 10.1098/rstb.2015.0487

Review

Authors: Justin P Kumar

The developing eye-antennal disc of Drosophila melanogaster has been studied for more than a century, and it has been used as a model system to study diverse processes, such as tissue specification, organ growth, programmed cell death, compartment boundaries, pattern formation, cell fate specification, and planar cell polarity. The findings that have come out of these studies have informed our understanding of basic developmental processes as well as human disease. For example, the isolation of a white-eyed fly ultimately led to a greater appreciation of the role that sex chromosomes play in development, sex determination, and sex linked genetic disorders. Similarly, the discovery of the Sevenless receptor tyrosine kinase pathway not only revealed how the fate of the R7 photoreceptor is selected but it also helped our understanding of how disruptions in similar biochemical pathways result in tumorigenesis and cancer onset. In this article, I will discuss some underappreciated areas of fly eye development that are fertile for investigation and are ripe for producing exciting new breakthroughs. The topics covered here include organ shape, growth control, inductive signaling, and right-left symmetry. Developmental Dynamics 247:111-123, 2018. © 2017 Wiley Periodicals, Inc.

Topics: Animals; Cell Differentiation; Drosophila Proteins; Drosophila melanogaster; Gene Expression Regulation, Developmental; Photoreceptor Cells, Invertebrate; Receptor Protein-Tyrosine Kinases; Retina; Signal Transduction

PubMed: 28856763
DOI: 10.1002/dvdy.24585

Authors: Susanna P Clement, Katharina Breher, Niklas Domdei...

PURPOSE

To determine whether light chromaticity without defocus induced by longitudinal chromatic aberration (LCA) is sufficient to regulate eye growth.

METHODS

An interferometric setup based on a spatial light modulator was used to illuminate the dominant eyes of 23 participants for 30 minutes with three aberration-free stimulation conditions: (1) short wavelength (450 nm), (2) long wavelength (638 nm), and (3) broadband light (450-700 nm), covering a retinal area of 12°. The non-dominant eye was occluded and remained as the control eye. Axial length and choroidal thickness were measured before and after the illumination period.

RESULTS

Axial length increased significantly from baseline for short-wavelength (P < 0.01, 7.4 ± 2.2 µm) and long-wavelength (P = 0.01, 4.8 ± 1.7 µm) light. The broadband condition also showed an increase in axial length with no significance (P = 0.08, 5.1 ± 3.5 µm). The choroidal thickness significantly decreased in the case of long-wavelength light (P < 0.01, -5.7 ± 2.2 µm), but there was no significant change after short-wavelength and broadband illumination. The axial length and choroidal thickness did not differ significantly between the test and control eyes or between the illumination conditions (all P > 0.05). Also, the illuminated versus non-illuminated choroidal zone did not show a significant difference (all P > 0.05).

CONCLUSIONS

All stimulation conditions with short- and long-wavelength light and broadband light led to axial elongation and choroidal thinning. Therefore, light chromaticity without defocus induced by LCA is suggested to be insufficient to regulate eye growth.

TRANSLATIONAL RELEVANCE

This study helps in understanding if light chromaticity alone is a sufficient regulator of eye growth.

Topics: Humans; Choroid; Female; Male; Axial Length, Eye; Adult; Young Adult; Light; Interferometry; Tomography, Optical Coherence; Photic Stimulation

PubMed: 38662401
DOI: 10.1167/tvst.13.4.30