Towards a Better Vision of Retinoic Acid Signaling during Eye Development

Abstract

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.

Zebrafish Model of Stickler Syndrome Suggests a Role for Col2a1a in the Neural Crest during Early Eye Development

“…As an essential morphogen and major regulator of cranial neural crest cells during embryogenesis, the tight control of retinoic acid (RA) mediates the migration and differentiation of these cells within the pharyngeal arches, frontonasal process, and periocular mesenchyme, which ultimately give rise to cranial bones and connective tissues as well as the structures in the ocular anterior segment [ 32 , 33 , 34 , 35 , 36 , 37 ]. Accordingly, we next examined the influence of alterations in RA levels on col2a1a expression in the ocular and craniofacial neural crest.…”

“…RA is a well-characterized regulator of embryonic craniofacial and ocular anterior segment formation [ 34 , 35 , 37 , 38 , 52 , 53 ]. Indeed, craniofacial and eye development requires highly regulated RA synthesis in the rhombencephalon and developing retina as well as the localized expression of the RA receptors (RARs) in the pharyngeal arches and periocular mesenchyme [ 22 , 54 , 55 , 56 ].…”

Generation of Lens Progenitor Cells and Lentoid Bodies from Pluripotent Stem Cells: Novel Tools for Human Lens Development and Ocular Disease Etiology

“…A subsequent reciprocal invagination of the non-neurogenic lens placode and neuroectoderm-derived optic vesicle generates the earliest 3D eye primordium, comprised of the lens vesicle and optic cup [ 28 , 30 , 34 ]. These eye primordia are surrounded by periocular mesenchymal cells, required subsequently for anterior segment morphogenesis [ 39 , 40 , 41 , 42 , 43 , 44 ] and covered by the surface ectoderm, giving rise to the corneal epithelium [ 45 ]. At its anterior portion, the polarized lens vesicle is patterned by gradients of BMP, FGF, IGF, PDGF, and Wnt growth factors.…”

All-trans retinoic acid modulates pigmentation, neuroretinal maturation, and corneal transparency in human multiocular organoids

“…All-trans retinoic acid (ATRA) is a metabolite of vitamin A (retinoids) that mediates functions required for eye growth and development during embryogenesis and vision [ 1 ]. ATRA functions as a morphogen signaling molecule that guides embryonic anterior/posterior axis formation of the eye during ocular development.…”