Endogenous retinoic acid signaling is required for maintenance and regeneration of cornea

Abstract

Retinoic acid (RA) is a biologically active metabolite of vitamin A (retinol) that serves as an important signaling molecule in orchestrating diverse developmental processes including multiple roles during ocular development. Loss-of-function studies using gene knockouts of RA-synthesizing enzymes encoded by Aldh1a1, Aldh1a2, and Aldh1a3 (also known as Raldh1, Raldh2, and Raldh3) have provided valuable insight into how RA controls eye morphogenesis including corneal development, however it is unclear whether endogenous RA is required for maintenance and regeneration of adult cornea. Here, we investigated the role of Aldh1a genes in the adult cornea using a novel conditional Aldh1a1,2,3-flox/flox;Rosa26-CreERT2 loss-of-function mouse model to determine the biological function of RA. Our findings indicate that loss of RA synthesis results in corneal thinning characterized by reduced thickness of the stromal layer, impaired corneal epithelial cell proliferation, and increased apoptosis. Corneal thinning in Aldh1a-deficient mice was significantly rescued by RA administration, indicating an important role of endogenous RA signaling in adult corneal homeostasis and regeneration. Thus, Aldh1a1,2,3-flox/flox;Rosa26-CreERT2 mice provide a useful model for investigating the mechanistic role of RA signaling in adult corneal maintenance and could provide new insights into therapeutic approaches for controlling corneal repair to prevent vision loss.

Differential epithelial and stromal protein profiles in cone and non-cone regions of keratoconus corneas

“…Besides its anti-oxidation activity, ADH7 participates in retinoic acid (RA) synthesis and retinoid X receptor (RXR) signalling 66 that could regulate stromal cell survival and matrix homeostasis. Loss of RA synthesis has been shown to reduce corneal stromal thickness and increase apoptosis, resulting in corneal thinning 67 . Additionally, the suppressed STEAP4 metalloproteinase could indicate mitochondrial damage and oxidative stress, affecting stromal keratocyte function and viability 68 .…”

A cell fitness selection model for neuronal survival during development

“…To prevent possible compensatory mechanisms for the loss of RALDH2 by ectopic expression of RALDH1 and RALDH3, we used a mutant mouse model in which the three members of the Raldh family are deleted conditionally: CAGG CreER ; Raldh1 fl/fl ; Raldh2 fl/fl ; Raldh3 fl/fl , hereafter named Raldh1/2/3 cKO . When induced by tamoxifen at E10, Raldh1/2/3 cKO mice do not need RA supplementation to survive 48 . However, this timing of induction does not permit the analysis at the brachial level, where RUNX3 expression is observed from E10.5.…”

“…Wild-type C57BL6 mice were used unless specified otherwise. Runx3 −/− , TrkC CreER , Raldh2 −/− , Raldh1 fl/fl , Raldh2 fl/fl , Raldh3 fl/fl and the CAGG CreERTM mouse strains have been described elsewhere 30,48,62–65 . Bax −/− , R26 CreERT2 , TrkC −/− and Ai14 mice have been purchased from Jackson Laboratories, and NT3 −/− and TrkC Cre from MMRRC.…”

Recent insights on the role and regulation of retinoic acid signaling during epicardial development

“…Even so, the great redundancy present in the retinoid metabolome, prevents us from establishing a complete list of the enzymes responsible for many important biotransformations of retinoids. Nonetheless, the knowledge of the main embryonic retinoid enzymes provides us with tools to study the roles of endogenous RA by manipulating its levels in tissue-specific manner through conditional gene targeting (Arregi et al, 2016;Beedle et al, 2019;Bonney, Dennison, Wendlandt, & Siegenthaler, 2018;Kumar, Dolle, Ghyselinck, & Duester, 2017).…”