Timeline of Developmental Defects Generated upon Genetic Inhibition of the Retinoic Acid Receptor Signaling Pathway

Abstract

It has been established for almost 30 years that the retinoic acid receptor (RAR) signalling pathway plays essential roles in the morphogenesis of a large variety of organs and systems. Here, we used a temporally controlled genetic ablation procedure to precisely determine the time windows requiring RAR functions. Our results indicate that from E8.5 to E9.5, RAR functions are critical for the axial rotation of the embryo, the appearance of the sinus venosus, the modelling of blood vessels, and the formation of forelimb buds, lung buds, dorsal pancreatic bud, lens, and otocyst. They also reveal that E9.5 to E10.5 spans a critical developmental period during which the RARs are required for trachea formation, lung branching morphogenesis, patterning of great arteries derived from aortic arches, closure of the optic fissure, and growth of inner ear structures and of facial processes. Comparing the phenotypes of mutants lacking the 3 RARs with that of mutants deprived of all-trans retinoic acid (ATRA) synthesising enzymes establishes that cardiac looping is the earliest known morphogenetic event requiring a functional ATRA-activated RAR signalling pathway.

Non-canonical retinoid signaling in neural development, regeneration and synaptic function

“…The importance of Vitamin A and retinoid signaling in developmental processes was confirmed with retinoid receptor mutants (which produced similar effects as Vitamin A deficiency). Indeed, the advancement of molecular genetic approaches allowed the induction of stage-specific deficiencies, providing insight into the importance of RA at specific developmental timepoints (Teletin et al, 2023 ). There is unique RAR expression during different stages of development (Huang et al, 2008 ; Linville et al, 2009 ) and retinoid signaling is under tight spatiotemporal control via regulation of the bioavailability of RA for receptor binding (Duester, 2008 ).…”

Genetic loss-of-function does not support gain-of-function studies suggesting retinoic acid controls limb bud timing and scaling

“…Subsequently, an article was published in 2007 by Sandell et al (2007) who generated a mouse mutant for Rdh10 encoding retinol dehydrogenase 10 (RDH10) that performs the first step of RA synthesis (retinol to retinaldehyde); Rdh10 mutant embryos survive long enough to develop limbs because they retain a small amount of trunk RA activity (probably due to another unknown retinol-metabolizing enzyme), but limb buds do not exhibit RA signaling activity and proximodistal patterning of hindlimbs is normal whereas forelimbs are stunted. Interestingly, a recent genetic LOF study shows that conditional incomplete loss of all three mouse RA receptors results in embryos with a stunted forelimb but a hindlimb of normal size similar to Rdh10 mutants ( Teletin et al, 2023 ). These mouse LOF studies suggest that loss of RA signaling does not effect the timing and scaling of limb buds, especially hindlimb buds.…”