Genetic architecture of retinoic-acid signaling-associated ocular developmental defects

Nédelec, Brigitte; Rozet, Jean–Michel; Taie, Lucas Fares

doi:10.1007/s00439-019-02052-2

Cited by 11 publications

(8 citation statements)

References 162 publications

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“…Vitamin A, in the form of retinol, is transported in serum by RBP4 , and its cellular uptake is facilitated by STRA6 (Blaner, 1989; Bouillet et al, 1997; Kawaguchi et al, 2007). Intracellularly, retinol is metabolized into RA by a group of alcohol dehydrogenases and aldehyde dehydrogenases, such as ALDH1A3 , after which a number of transcriptional responses is mediated by RA (Nedelec, Rozet, & Fares Taie, 2019). Investigations of Aldh1a1 ( Raldh1 ), Aldh1a2 ( Raldh2 ), and Aldh1a3 ( Raldh3 ) in mice show that disruption of RA synthesis genes result in the failure of the optic vesicle invagination (Mic, Molotkov, Molotkova, & Duester, 2004; Molotkov, Molotkova, & Duester, 2006).…”

Section: Migration Of Retinal Precursors To Form Optic Cupmentioning

confidence: 99%

Ocular coloboma: Genetic variants reveal a dynamic model of eye development

Yoon

Fox

Dicipulo

et al. 2020

American J of Med Genetics Pt C

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Ocular coloboma is a congenital disorder of the eye where a gap exists in the inferior retina, lens, iris, or optic nerve tissue. With a prevalence of 2-19 per 100,000 live births, coloboma, and microphthalmia, an associated ocular disorder, represent up to 10% of childhood blindness. It manifests due to the failure of choroid fissure closure during eye development, and it is a part of a spectrum of ocular disorders that include microphthalmia and anophthalmia. Use of genetic approaches from classical pedigree analyses to next generation sequencing has identified more than 40 loci that are associated with the causality of ocular coloboma. As we have expanded studies to include singleton cases, hereditability has been very challenging to prove. As such, researchers over the past 20 years, have unraveled the complex interrelationship amongst these 40 genes using vertebrate model organisms. Such research has greatly increased our understanding of eye development. These genes function to regulate initial specification of the eye field, migration of retinal precursors, patterning of the retina, neural crest cell biology, and activity of head mesoderm. This review will discuss the discovery of loci using patient data, their investigations in animal models, and the recent advances stemming from animal models that shed new light in patient diagnosis.

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Section: Migration Of Retinal Precursors To Form Optic Cupmentioning

confidence: 99%

Ocular coloboma: Genetic variants reveal a dynamic model of eye development

Yoon

Fox

Dicipulo

et al. 2020

American J of Med Genetics Pt C

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“…The reciprocal relationship between RA signaling and mammalian eye development has been well-described over the past few decades [70,[89][90][91][92][93].…”

Section: Ra Signaling-associated Eye Development and Raldh-relevant Aop (Aop 297 )mentioning

confidence: 99%

Retinaldehyde Dehydrogenase Inhibition-Related Adverse Outcome Pathway: Potential Risk of Retinoic Acid Synthesis Inhibition during Embryogenesis

Cho

Lee

Heo³

et al. 2021

Toxins

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Retinoic acid (RA) is one of the factors crucial for cell growth, differentiation, and embryogenesis; it interacts with the retinoic acid receptor and retinoic acid X receptor to eventually regulate target gene expression in chordates. RA is transformed from retinaldehyde via oxidization by retinaldehyde dehydrogenase (RALDH), which belongs to the family of oxidoreductases. Several chemicals, including disulphiram, diethylaminobenzaldehyde, and SB-210661, can effectively inhibit RALDH activity, potentially causing reproductive and developmental toxicity. The modes of action can be sequentially explained based on the molecular initiating event toward key events, and finally the adverse outcomes. Adverse outcome pathway (AOP) is a conceptual and theoretical framework that describes the sequential chain of casually liked events at different biological levels from molecular events to adverse effects. In the present review, we discussed a recently registered AOP (AOP297; inhibition of retinaldehyde dehydrogenase leads to population decline) to explain and support the weight of evidence for RALDH inhibition-related developmental toxicity using the existing knowledge.

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“…Thus, RA regulates transcriptional activation or repression through RARE enhancers or RARE silencers [11]. RA controls critical functions during eye development in humans, mice, and zebrafish [12][13][14][15][16]. Human studies have associated mutations in four components of the RA signaling pathway (RBP4, STRA6, ALDH1A3, RARB) and two genes up-regulated by RA (PITX2, FOXC1) with anophthalmia/microphthalmia [12][13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

“…RA controls critical functions during eye development in humans, mice, and zebrafish [12][13][14][15][16]. Human studies have associated mutations in four components of the RA signaling pathway (RBP4, STRA6, ALDH1A3, RARB) and two genes up-regulated by RA (PITX2, FOXC1) with anophthalmia/microphthalmia [12][13][14][15][16][17]. However, studies on mouse embryos will likely identify additional RA target genes.…”

Section: Introductionmentioning

confidence: 99%

Towards a Better Vision of Retinoic Acid Signaling during Eye Development

Duester

2022

Cells

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Retinoic acid (RA) functions as an essential signal for development of the vertebrate eye by controlling the transcriptional regulatory activity of RA receptors (RARs). During eye development, the optic vesicles and later the retina generate RA as a metabolite of vitamin A (retinol). Retinol is first converted to retinaldehyde by retinol dehydrogenase 10 (RDH10) and then to RA by all three retinaldehyde dehydrogenases (ALDH1A1, ALDH1A2, and ALDH1A3). In early mouse embryos, RA diffuses to tissues throughout the optic placode, optic vesicle, and adjacent mesenchyme to stimulate folding of the optic vesicle to form the optic cup. RA later generated by the retina is needed for further morphogenesis of the optic cup and surrounding perioptic mesenchyme; loss of RA at this stage leads to microphthalmia and cornea plus eyelid defects. RA functions by binding to nuclear RARs at RA response elements (RAREs) that either activate or repress transcription of key genes. Binding of RA to RARs regulates recruitment of transcriptional coregulators such as nuclear receptor coactivator (NCOA) or nuclear receptor corepressor (NCOR), which in turn control binding of the generic coactivator p300 or the generic corepressor PRC2. No genes have been identified as direct targets of RA signaling during eye development, so future studies need to focus on identifying such genes and their RAREs. Studies designed to learn how RA normally controls eye development in vivo will provide basic knowledge valuable for determining how developmental eye defects occur and for improving strategies to treat eye defects.

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Genetic architecture of retinoic-acid signaling-associated ocular developmental defects

Cited by 11 publications

References 162 publications

Ocular coloboma: Genetic variants reveal a dynamic model of eye development

Ocular coloboma: Genetic variants reveal a dynamic model of eye development

Retinaldehyde Dehydrogenase Inhibition-Related Adverse Outcome Pathway: Potential Risk of Retinoic Acid Synthesis Inhibition during Embryogenesis

Towards a Better Vision of Retinoic Acid Signaling during Eye Development

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