Retinol dehydrogenase 10 is a feedback regulator of retinoic acid signalling during axis formation and patterning of the central nervous system

Abstract

Retinoic acid (RA) is an important morphogen that regulates many biological processes, including the development of the central nervous system (CNS). Its synthesis from vitamin A (retinol) occurs in two steps, with the second reaction -catalyzed by retinal dehydrogenases (RALDHs) -long considered to be crucial for tissue-specific RA production in the embryo. We have recently identified the Xenopus homologue of retinol dehydrogenase 10 (XRDH10) that mediates the first step in RA synthesis from retinol to retinal. XRDH10 is specifically expressed in the dorsal blastopore lip and in other domains of the early embryo that partially overlap with XRALDH2 expression. We show that endogenous RA suppresses XRDH10 gene expression, suggesting negativefeedback regulation. In mRNA-injected Xenopus embryos, XRDH10 mimicked RA responses, influenced the gene expression of organizer markers, and synergized with XRALDH2 in posteriorizing the developing brain. Knockdown of XRDH10 and XRALDH2 by specific antisense morpholino oligonucleotides had the opposite effects on organizer gene expression, and caused a ventralized phenotype and anteriorization of the brain. These data indicate that the conversion of retinol into retinal is a developmentally controlled step involved in specification of the dorsoventral and anteroposterior body axes, as well as in pattern formation of the CNS. We suggest that the combinatorial gene expression and concerted action of XRDH10 and XRALDH2 constitute a 'biosynthetic enzyme code' for the establishment of a morphogen gradient in the embryo.

Heat Shock 70-kDa Protein 5 (Hspa5) Is Essential for Pronephros Formation by Mediating Retinoic Acid Signaling

“…In the control animal caps, atRA treatment led to an up-regulation of expression in RA-responsive genes including lhx1, cdx4, and gbx2 (Fig. 6A, lane 3) (37,48). In contrast, RA-induced up-reg- A, schematic diagram of in vitro pronephros induction assay showing animal caps are induced to differentiate into pronephros tissues using atRA and activin.…”

Retinoic acid signalling during development

“…Studies in Xenopus proposed an alternative mode of RA gradient formation based on cooperation between RDH10 and RALDH2 (Strate et al, 2009). RDH10 produces retinaldehyde in the anterior cervical mesoderm and ventral hindbrain that diffuses posteriorly, where RALDH2 converts it into RA.…”

The expression of Stra6 and Rdh10 in the avian embryo and their contribution to the generation of retinoid signatures

“…The second class of localisation are those regions which superficially show co-expression, but actually reveal an interesting phenomenon recently described in Xenopus (Strate et al 2009) where the domain of the Raldh is much more extensive than that of Rdh10. These regions include the eye, the somites and the early mesoderm and the expression patterns are summarised in Fig.…”

“…5B. This phenomenon has been seen in Xenopus early mesoderm and led to the suggestion that retinal diffuses from the Rdh10 expressing cells into the Raldh2 expressing (Rdh10 negative) posterior cells (Strate et al 2009). This novel concept means that not only does RA diffuse across fields of cells but so does its precursor, retinal and it will be important to conduct tests of this hypothesis.…”

“…Stra6 seems to be widely distributed in the mouse embryo (Bouillet et al 1997), but little is known about its precise relationship to the other components of the RA synthetic pathway and here we describe precise and overlaps with many sites of RALDH expression but also has some unique localisations such as the floorplate of the neural tube and the zone of polarizing activity in the forelimb bud, sites of no known Raldh expression. Rdh10 has also been described in the Xenopus embryo (Strate et al 2009) where its expression shows differences from the mouse and its levels are regulated by excess RA and reduced RA concentrations. Here we describe the expression and regulation by RA of Rdh10 in the early chick embryo and vitamin A-deficient (VAD) quail embryo along with that of Stra6 and ask whether they are coordinated together with the Raldhs in RA-responsive developing fields.…”