ADHFe1: a novel enzyme involved in retinoic acid-dependent Hox activation

Abstract

Retinoic acid (RA) signaling is a central pathway regulating anterior-posterior patterning of the embryo through its targets, the Hox genes. RA is produced by two sequential oxidations from vitamin A (retinol) and this biosynthesis has to be regulated temporally, spatially and quantitatively. Mining Xenopus embryonic expression databases identified a novel component of the RA metabolic network, ADHFe1. Using Xenopus laevis embryos as our experimental system we determined the temporal and spatial pattern of AdhFe1 expression. Gain- and loss-of-function of ADHFe1 were induced to study its function and the regulation of the AdhFe1 gene by RA was studied. Expression analysis localized the ADHFe1 protein to the late Spemann's organizer, the trunk organizer. Subsequently, ADHFe1 can be detected in the prechordal mesoderm, the notochord and the lateral plate mesoderm. Manipulation of ADHFe1 levels affects the normal Hox gene expression. The effects of ADHFe1 manipulation can by rescued by increasing the levels of RA or its biosynthesis. Expression of the AdhFe1 gene is regulated by RA itself. ADHFe1 is an enzyme active already during gastrula stages and the protein is still present during neurula stages. ADHFe1 regulates the expression of the Hox genes during the early patterning of the trunk. The effect of ADHFe1 on Hox expression is mediated through regulation of RA levels. ADHFe1 probably reduces retinaldehyde to retinol thereby restricting the availability of retinaldehyde, the substrate needed by retinaldehyde dehydrogenases to produce RA making it a novel regulator of RA concentrations in the embryo and RA homeostasis.

Retinoic acid fluctuation activates an uneven, direction-dependent network-wide robustness response in early embryogenesis

“…Some of the differences between them apparently include enzymatic efficiencies and their expression patterns including location, timing, and intensity (Blentic et al, 2003; Chen et al, 2001; Lupo et al, 2005; Romand et al, 2004; Shabtai et al, 2018). A similar situation can be argued for enzymes with RA degrading or biosynthetic suppressing activity like CYP26A1, B1, and C1, or DHRS3, ADHFe1, RDH13 and others (Belyaeva et al, 2017, 2008; Hollemann et al, 1998; Shabtai et al, 2017; Sonneveld et al, 1998). Some of these enzymes can reduce or prevent the production of retinaldehyde while others make the RA biologically inactive targeting it for degradation.…”

“…Multiple reports have described the regulation of RA network component expression by RA itself. Most of these studies deal with RA treatments resulting in the up-regulation of enzymes involved in the suppression or reduction of RA signaling like CYP26A1, ADHFe1, and DHRS3, and down-regulation of RA producers (anabolic enzymes) like RALDH2 and RDH10 (Chen et al, 2001; Dobbs-McAuliffe et al, 2004; Fujii et al, 1997; Hollemann et al, 1998; Kam et al, 2013; Sandell et al, 2012; Shabtai et al, 2017; Sonneveld et al, 1998; Strate et al, 2009).…”

“…Analysis of RA target genes and genes encoding components of the RA metabolic and signaling network suggests that the RA metabolic network through an RA-dependent feedback regulatory mechanism is altered in an attempt to restore normal signaling levels. Multiple reports have described the regulation of individual RA network components by RA itself (Chen et al, 2001; Dobbs-McAuliffe et al, 2004; Fujii et al, 1997; Hollemann et al, 1998; Kam et al, 2013; Sandell et al, 2012; Shabtai et al, 2017; Sonneveld et al, 1998; Strate et al, 2009). Our results provide an integrative network-wide view that incorporates the concerted feedback regulation of multiple pathway components to achieve normal signaling under changing environmental conditions.…”

Insights into retinoic acid deficiency and the induction of craniofacial malformations and microcephaly in fetal alcohol spectrum disorder

“…This group of cells, the head‐inducing prechordal mesoderm, have been shown to express one of the retinoic acid producing enzymes, retinaldehyde dehydrogenase 3 (RALDH3; ALDH1A3) (Lupo et al, ). In addition, before or early in their rostral migration, the amphibian organizer expresses multiple components of the retinoic acid biosynthetic network including RALDH2 (Chen, Pollet, Niehrs, & Pieler, ), RALDH3 (Lupo et al, ), RDH10 (Strate et al, ), DHRS3 (Richard K T Kam et al, ), and ADHFe1 (Shabtai, Shukrun, & Fainsod, ). Some of these components have also been described in other vertebrate embryos in analogous regions or their vicinity (Begemann et al, ; Blentic, Gale, & Maden, ; Grandel et al, ; Liang et al, ; Metzler & Sandell, ; Niederreither, Fraulob, Garnier, Chambon, & Dollé, ; Niederreither, McCaffery, Dräger, Chambon, & Dollé, ; Pittlik, Domingues, Meyer, & Begemann, ; Sandell et al, ; Swindell et al, ).…”

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

“…Beside SDR enzymes, hydroxyacid-oxoacid transhydrogenase ADHFe1, a member of the iron-containing alcohol dehydrogenase family of enzymes, has been shown to control Hox gene expression via RA in X. laevis suggesting a potential role in RA metabolism (Shabtai, Shukrun, & Fainsod, 2017). Cytosolic medium chain alcohol dehydrogenases have also been proposed to contribute to the oxidation of retinol but do not appear to play a significant role during embryogenesis (Pares, Farres, Kedishvili, & Duester, 2008).…”