Retinoic Acid Maintains Function of Neural Crest–Derived Ocular and Craniofacial Structures in Adult Zebrafish

Abstract

PurposeRetinoic acid (RA) is required for embryonic formation of the anterior segment of the eye and craniofacial structures. The present study further investigated the role of RA in maintaining the function of these neural crest–derived structures in adult zebrafish.MethodsMorphology and histology were analyzed by using live imaging, methylacrylate sections, and TUNEL assay. Functional analysis of vision and aqueous humor outflow were assayed with real-time imaging.ResultsBoth decreased and increased RA signaling altered craniofacial and ocular structures in adult zebrafish. Exogenous treatment with all-trans RA for 5 days resulted in a prognathic jaw, while inhibition of endogenous RA synthesis through treatment with 4-diethylaminobenzaldehyde (DEAB) decreased head height. In adult eyes, RA activity was localized to the retinal pigment epithelium, photoreceptors, outer plexiform layer, inner plexiform layer, iris stroma, and ventral canalicular network. Exogenous RA increased apoptosis in the iris stroma and canalicular network in the ventral iridocorneal angle, resulting in the loss of these structures and decreased aqueous outflow. DEAB, which decreased RA activity throughout the eye, induced widespread apoptosis, resulting in corneal edema, cataracts, retinal atrophy, and loss of iridocorneal angle structures. DEAB-treated fish were blind with no optokinetic response and no aqueous outflow from the anterior chamber.ConclusionsTight control of RA levels is required for normal structure and function of the adult anterior segment. These studies demonstrated that RA plays an important role in maintaining ocular and craniofacial structures in adult zebrafish.

The Ocular Neural Crest: Specification, Migration, and Then What?

“…However, much of the evidence pertains to the genetic networks responsible for ectodermal and neurectodermal patterning, and little is known about the specification of the ocular NC. Indeed, the continued requirement of NC stem cells for the maintenance of adult eyes ( Jinno et al, 2010 ; Green et al, 2015 ; Chawla et al, 2018 ) emphasizes the importance of this cell population over the vertebrate lifetime. This review will provide an update of the morphogenetic, gene regulation and signaling events controlling ocular NC migration and differentiation, with particular emphasis on the ocular anterior segment.…”

Spatiotemporal characterization of periocular mesenchyme heterogeneity during anterior segment development

“…Pitx2 in particular has been associated with the survival and migration of NCCs, as well as the development of the optic stalk, establishment of angiogenic privilege within the cornea, and craniofacial development (10, 11, 14, 17–21). FoxC1 and pitx2 are also known to interact with one another and their expression is regulated by retinoic acid signaling (13, 22, 23). Not surprisingly, mutations in NCC regulatory genes have also been associated with ASD.…”

What's retinoic acid got to do with it? Retinoic acid regulation of the neural crest in craniofacial and ocular development

“…In a recent study, we showed that in neural crest-derived craniofacial and ocular tissues, there is a continued need for RA in maintaining the function and integrity of these structures (Chawla, Swain, Williams, & Bohnsack, 2018 including the cornea and iridocorneal angle, which resulted in decreased aqueous outflow from the eyes (Chawla et al, 2018). This study represents the first evidence for the tight control of RA levels to maintain the normal structure and function of the anterior segment of the adult eye.…”

“…Chawla, Swain, Williams, & Bohnsack, 2018). In adult zebrafish, the neural crest-derived craniofacial bones, including the jaw and frontal bone, are highly sensitive to exogenous RA and the inhibition of endogenous RA synthesis.…”