Lens-regulated retinoic acid signalling controls expansion of the developing eye

Abstract

Absence of the developing lens results in severe eye defects, including substantial reductions in eye size. How the lens controls eye expansion and the underlying signalling pathways are very poorly defined. We identified RDH10, a gene crucial for retinoic acid synthesis during embryogenesis, as a key factor downregulated in the peripheral retina (presumptive ciliary body region) of lens-removed embryonic chicken eyes prior to overt reductions in eye size. This is associated with a significant decrease in retinoic acid synthesis by lens-removed eyes. Restoring retinoic acid signalling in lens-removed eyes by implanting beads soaked in retinoic acid or retinal, but not vitamin A, rescued eye size. Conversely, blocking retinoic acid synthesis decreased eye size in lens-containing eyes. Production of collagen II and collagen IX, which are major vitreal proteins, is also regulated by the lens and retinoic acid signalling. These data mechanistically link the known roles of both the lens and retinoic acid in normal eye development, and support a model whereby retinoic acid production by the peripheral retina acts downstream of the lens to support vitreous production and eye expansion.

Canonical NF-κB signaling maintains corneal epithelial integrity and prevents corneal aging via retinoic acid

“…Mechanistically, NF-B positively regulated Aldh1a1 transcription and retinoic acid (RA) synthesis from vitamin A and that the development of corneal phenotypes in Rela-deficient mice or naturally aged mice was largely prevented by RA administration. While vitamin A deficiency is known to cause night blindness, corneal ulcers, and eye development defects, mainly in children (35)(36)(37)(38)(39), we show for the first time that RA, the metabolic product of vitamin A, is critical in corneal regeneration and aging in mice, implying that RA has the potential to improve corneal health in adult and aged individuals.…”

“…Previous studies have shown that RA plays a role in eye development, likely via the Wnt--Catenin pathway (35,61,62), which involves in corneal stromal cells (24,35,44).…”

Limitations and Promise of Retinal Tissue From Human Pluripotent Stem Cells for Developing Therapies of Blindness

“…Developing retinal organoids (even without RPE) seem to be a good model for dissecting such major cell fate decisions, cell cycle, number of progenitors of each cell type and their initial organization in developing mammalian retina. Nevertheless, one should be mindful of some differences such as lack of RPE and lens and changes in the extrinsic factors and morphogen gradients caused by these differences ( Dakubo et al, 2008 ; Smith et al, 2018 ). Though these signaling cues have some major consequences for translational research (e.g., BMP/TGFb signaling from ocular surface ectoderm through Smad4, also modulated HH signaling ( Li et al, 2016 ), these are very early developmental processes (NR vs RPE), typically related to microphthalmia ( Bharti et al, 2006 ; Manuel et al, 2008 ; Bharti et al, 2012 ) and marginally related to RD diseases.…”

Sonic Hedgehog Signaling Is Required for Cyp26 Expression during Embryonic Development

“…The Hedgehog and retinoic acid (RA) signaling pathways play key roles during embryogenesis, organogenesis, and tissue homeostasis [1,2,3,4,5,6,7,8,9,10,11,12,13], and genetic disruption of Hedgehog signaling can lead to neoplasia [1,14,15,16,17,18]. Mammals produce three Hedgehog ligands, Desert hedgehog, Indian hedgehog (IHH) and Sonic hedgehog (SHH) [1,19].…”