Abstract
Retinoic Acid (RA) is a small lipophilic signaling molecule essential for embryonic development and adult tissue maintenance. Both an excess of RA and a deficiency of RA can cause pathogenic anomalies, hence it is critical to understand the mechanisms controlling the spatial and temporal distribution of RA. However, our current understanding of these processes remains incomplete. Vitamin A is metabolized to RA via two sequential enzymatic reactions. The first requires retinol dehydrogenase (RDH) activity to oxidize Vitamin A (retinol) to retinal, and the second requires retinaldehyde activity (RALDH) to oxidize retinal into RA. The first reaction has previously been attributed to the alcohol dehydrogenase (ADH) family, whose genes are ubiquitously or redundantly expressed. Consequently, the specificity of RA synthesis was thought to reside exclusively at the level of the second reaction. To better understand the metabolism of Vitamin A into RA during embryogenesis, we generated new mouse models that disrupt this process. Here we describe a new targeted knockout of Rdh10 in which RA synthesis is severely impaired, particularly at critical early embryonic stages. We also introduce a new mutant allele of Aldh1a2. Both mutations produce similar developmental defects resulting in lethality around embryonic day 10.5 (E10.5). The severity of the Rdh10 null phenotype demonstrates that embryonic oxidation of retinol is carried out primarily by RDH10 and that neither ADHs nor other enzymes contribute significantly to this reaction. We also show that reduced RA production results in upregulation of Rdh10. These data demonstrate that RDH10 plays a critical role in mediating the rate limiting RDH step of Vitamin A metabolism and functions as a nodal point in feedback regulation of RA synthesis. Moreover, RDH10-mediated oxidation of retinol plays as important a role in the control and regulation of RA production during embryogenesis as does the subsequent RALDH-mediated reaction.
Highlights
Retinoic acid (RA) is a derivative of Vitamin A that plays an essential role in many vertebrate biological processes including energy metabolism, brain function, immune response, reproduction and embryonic development
At E10.5 a reduction in size of the forelimb bud and absence of posterior pharyngeal arches are clearly evident (Fig. 1E). This constellation of defects observed in the Rdh10trex/trex embryos is consistent with retinoid deficiency but is less severe than that observed in embryos in which RALDH2 function has been eliminated
Two sequential enzymatic steps are required for metabolism of retinol into RA, the retinol dehydrogenase (RDH) first reaction and the retinaldehyde dehydrogenase activity (RALDH) second reaction (Fig. 6C)
Summary
Retinoic acid (RA) is a derivative of Vitamin A (retinol) that plays an essential role in many vertebrate biological processes including energy metabolism, brain function, immune response, reproduction and embryonic development (reviewed in [1,2,3, 4,5,6]). Expression of Rdh is regulated spatially and temporally in a pattern overlapping with the retinol transporter Stra, but does not appear to be regulated by feedback from excessive or reduced levels of RA [26] These recent findings raise questions of the specific contribution of RDH10 versus ADHs and of the true mechanistic importance of the first oxidation step of Vitamin A metabolism in controlling embryonic RA synthesis. In this report we find that Rdh gene expression is elevated when RA levels are reduced, providing evidence that Rdh functions as a control point for feedback regulation of the RA synthesis pathway in mammals These data demonstrate that the initial RDH reaction of Vitamin A metabolism, mediated primarily by RDH10, plays as critical a role in embryogenesis and is as important in the control and regulation of RA production as is the subsequent RALDH reaction
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