Early retinoic acid deprivation in developing zebrafish results in microphthalmia

Le, Hong-Gam; Dowling, John E.; Cameron, D. Joshua

doi:10.1017/s0952523812000296

Cited by 37 publications

(37 citation statements)

References 39 publications

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“…RAR mutations and vitamin A deficiency in early development result in ocular coloboma and microphthalmia, among other eye defects (35). Although inhibition of RA signaling in zebrafish at earlier developmental stages results in disruption or delay of retinal development and microphthalmia (36,37), inhibition of RA signaling beginning at 2 dpf in our study had no significant effect on eye size (Supplemental Fig. 1E).…”

Section: Discussionmentioning

confidence: 52%

Retinoic acid signaling is essential for maintenance of the blood‐retinal barrier

et al. 2018

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The predominant function of the blood-retinal barrier (BRB) is to maintain retinal homeostasis by regulating the influx and efflux between the blood and retina. Breakdown of the BRB occurs in a number of ocular diseases that result in vision loss. Understanding the molecular and cellular pathways involved in the development and maintenance of the BRB is critical to developing therapeutics for these conditions. To visualize the BRB in vivo, we used the transgenic Tg(l-fabp:DBP-EGFP:flk1:mCherry) zebrafish model that expresses vitamin D binding protein (a member of the albumin gene family) tagged to green fluorescent protein. Retinoic acid (RA) plays a number of important roles in vertebrate development and has been shown to play a protective role during inflammation-induced blood-brain barrier disruption. The role of RA in BRB development and maintenance remains unknown. To disrupt RA signaling, Tg(l-fabp:DBP-EGFP:flk1:mCherry) zebrafish were treated with N, N-diethylaminobenzaldehyde and 4-[(1 E)-2-[5,6-dihydro-5,5-dimethyl-8-(2-phenylethynyl)-2-naphthalenyl]ethenyl]benzoic acid, which are antagonists of retinal dehydrogenase and the RA receptor, respectively. Treatment with either compound resulted in BRB disruption and reduced visual acuity, whereas cotreatment with all- trans RA effectively rescued BRB integrity. Additionally, transgenic overexpression of Cyp26a1, which catalyzes RA degradation, resulted in breakdown of the BRB. Our results demonstrate that RA signaling is critical for maintenance of the BRB and could play a role in diseases such as diabetic macular edema.-Pollock, L. M., Xie, J., Bell, B. A., Anand-Apte, B. Retinoic acid signaling is essential for maintenance of the blood-retinal barrier.

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Section: Discussionmentioning

confidence: 52%

Retinoic acid signaling is essential for maintenance of the blood‐retinal barrier

et al. 2018

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“…Microphthalmia and ocular hypertelorism were the other toxic effects induced by the MCP in zebrafish embryos. The retinoic acid deprivation and inhibition of Alx1 gene in developing zebrafish embryos could be the reason for microphthalmia and hypertelorism, respectively (Le et al 2012;Dee et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Developmental toxic effects of monocrotophos, an organophosphorous pesticide, on zebrafish (Danio rerio) embryos

Pamanji

Bethu

Yashwanth

et al. 2015

Environ Sci Pollut Res

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The present study examined the response of zebrafish embryos exposed to different concentrations (10, 20, 30, 40, 50, and 60 mg/L) of monocrotophos under static conditions for 96 h. We found that mortality had occurred within 48 h at all test concentrations, later insignificant mortality was observed. Monocrotophos (MCP) can be rated as moderately toxic to the Zebrafish embryos with a 96-h median lethal concentration (LC50) of 37.44 ± 3.32 mg/L. In contrast, it greatly affected the development of zebrafish embryos by inducing several developmental abnormalities like pericardial edema, altered heart development, spinal and vertebral anomalies in a concentration-dependent manner. A significant percent reduction in length by 9-48% and heart beats by 18-51% was observed in hatchlings exposed to LC10 and LC50 concentrations at 96 h when compared to controls. The process of looping formation of heart at embryonic stage was greatly affected by the LC50 concentration of MCP. The neurotoxic potentiality of MCP was assessed by using a marker enzyme, acetylcholinesterase in both in vitro and in vivo experiments. MCP was found to be the most potent inhibitor of AChE in vitro with an IC50 value of 4.3 × 10(-4) M. The whole-body AChE enzyme activity in vivo was significantly inhibited during the exposure tenure with the maximum inhibition of 62% at 24 h.

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“…Many studies combine the use of behavioral measures such as testing of the optomotor reflex to obtain visual acuity and contrast sensitivity data with physiological readouts such as electroretinography or structural assays such as OCT to obtain a more comprehensive overall assessment of retinal and neuronal health of a given subject. These methods have been employed in combination to assess visual differences amongst mouse strains (Puk et al, 2008), visual deficits in zebrafish models (Allwardt et al, 2001; Bahadori et al, 2006; Biehlmaier et al, 2007; Bilotta et al, 2002; Brockerhoff, 2006; Brockerhoff et al, 1995; Kainz et al, 2003; Le et al, 2012; Stujenske et al, 2011; Van Epps et al, 2001), therapeutic effects of compounds in goldfish (Mora-Ferrer et al, 2005), normal retinal function (Ho et al, 2012), therapies in visually impaired mice (Boye et al, 2010) and rats (McGill et al, 2007). The correlation of these parameters with morphological changes in the retina (McGill et al, 2012a; McGill et al, 2012b), was used to assess changes during retinal degeneration (Barabas et al, 2013; Cammas et al, 2010; Pang et al, 2011; Samardzija et al, 2014; Wright et al, 2013) and dysfunction (Hoelter et al, 2008; Lodha et al, 2010), eye blast trauma (Bricker-Anthony et al, 2014), visual deficits in diabetes mouse (Aung et al, 2013; Aung et al, 2014) and rat models, after transgenic modification of RGCs (Tomita et al, 2010) or bipolar cells (Lagali et al, 2008) or after transplanting photoreceptors in the retina to improve vision (Schmucker and Schaeffel, 2006; Thompson et al, 2014).…”

Section: Future Developmentsmentioning

confidence: 99%

Psychophysical testing in rodent models of glaucomatous optic neuropathy

Grillo

Koulen

2015

Experimental Eye Research

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Processing of visual information begins in the retina, with photoreceptors converting light stimuli into neural signals. Ultimately, signals are transmitted to the brain through signaling networks formed by interneurons, namely bipolar, horizontal and amacrine cells providing input to retinal ganglion cells (RGCs), which form the optic nerve with their axons. As part of the chronic nature of glaucomatous optic neuropathy, the increasing and irreversible damage and ultimately loss of neurons, RGCs in particular, occurs following progressive damage to the optic nerve head (ONH), eventually resulting in visual impairment and visual field loss. There are two behavioral assays that are typically used to assess visual deficits in glaucoma rodent models, the visual water task and the optokinetic drum. The visual water task can assess an animal’s ability to distinguish grating patterns that are associated with an escape from water. The optokinetic drum relies on the optomotor response, a reflex turning of the head and neck in the direction of the visual stimuli, which usually consists of rotating black and white gratings. This reflex is a physiological response critical for keeping the image stable on the retina. Driven initially by the neuronal input from direction-selective RGCs, this reflex is comprised of a number of critical sensory and motor elements. In the presence of repeatable and defined stimuli, this reflex is extremely well suited to analyze subtle changes in the circuitry and performance of retinal neurons. Increasing the cycles of these alternating gratings per degree, or gradually reducing the contrast of the visual stimuli, threshold levels can be determined at which the animal is no longer tracking the stimuli, and thereby visual function of the animal can be determined non-invasively. Integrating these assays into an array of outcome measures that determine multiple aspects of visual function is a central goal in vision research and can be realized, for example, by the combination of measuring optomotor reflex function with electroretinograms (ERGs) and optical coherence tomography (OCT) of the retina. These structure-function correlations in vivo are urgently needed to identify disease mechanisms as potential new targets for drug development. Such a combination of the experimental assessment of the optokinetic reflex (OKN) or optomotor reflex (OMR) with other measures of retinal structure and function is especially valuable for research on GON. The chronic progression of the disease is characterized by a gradual decrease in function accompanied by a concomitant increase in structural damage to the retina, therefore the assessment of subtle changes is key to determining the success of novel intervention strategies.

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Early retinoic acid deprivation in developing zebrafish results in microphthalmia

Cited by 37 publications

References 39 publications

Retinoic acid signaling is essential for maintenance of the blood‐retinal barrier

Retinoic acid signaling is essential for maintenance of the blood‐retinal barrier

Developmental toxic effects of monocrotophos, an organophosphorous pesticide, on zebrafish (Danio rerio) embryos

Psychophysical testing in rodent models of glaucomatous optic neuropathy

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