Abstract
Retinoic acid (RA) is a major regulatory signal during embryogenesis produced from vitamin A (retinol) by an extensive, autoregulating metabolic and signaling network to prevent fluctuations that result in developmental malformations. Xenopus laevis is an allotetraploid hybrid frog species whose genome includes L (long) and S (short) chromosomes from the originating species. Evolutionarily, the X. laevis subgenomes have been losing either L or S homoeologs in about 43% of genes to generate singletons. In the RA network, out of the 47 genes, about 47% have lost one of the homoeologs, like the genome average. Interestingly, RA metabolism genes from storage (retinyl esters) to retinaldehyde production exhibit enhanced gene loss with 75% singletons out of 28 genes. The effect of this gene loss on RA signaling autoregulation was studied. Employing transient RA manipulations, homoeolog gene pairs were identified in which one homoeolog exhibits enhanced responses or looser regulation than the other, while in other pairs both homoeologs exhibit similar RA responses. CRISPR/Cas9 targeting of individual homoeologs to reduce their activity supports the hypothesis where the RA metabolic network gene loss results in tighter network regulation and more efficient RA robustness responses to overcome complex regulation conditions.
Highlights
Retinoic acid (RA) signaling is one of the major regulatory pathways active during embryogenesis and it controls numerous developmental processes [1–4]
In a recent extensive data mining effort searching the KEGG and Xenbase databases [44,52] and the literature, we assembled the putative components of the RA metabolic and signaling network assembling components described in multiple experimental systems and tissues [1,6,9]
To determine the composition of the RA network active during gastrula in Xenopus laevis embryos we assessed which components are expressed during this developmental stage based on analysis of transcriptomic data sets [27,53,54] and corroborated the gastrula expression by quantitative RT-PCR [27]
Summary
Retinoic acid (RA) signaling is one of the major regulatory pathways active during embryogenesis and it controls numerous developmental processes [1–4]. RA is produced in the body from nutritional sources containing vitamin A (retinol, ROL) and other retinoids, or carotenoids [5,6]. This metabolic network involves multiple enzymes active in the conversion of these substrates into RA, or the storage of retinoids as retinyl esters to survive periods when the nutritional sources of retinoids or carotenoids are diminished or lacking [5,7–10]. Increased or decreased RA signaling levels can result in severe developmental malformations [8,11–14]. For this reason, the RA metabolic and signaling network exhibits efficient self-regulation to overcome fluctuations in this signaling pathway elicited by dietary changes, environmental toxicity, or genetic polymorphisms [15–26]. The autoregulation of the RA network by RA levels is instrumental to maintaining pathway robustness in response to hampering mechanisms [27,28]
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