Regionalized metabolic activity establishes boundaries of retinoic acid signalling

Hollemann, Thomas; Chen, Yonglong; Grunz, Horst; Pieler, Tomas

doi:10.1093/emboj/17.24.7361

Cited by 156 publications

(193 citation statements)

References 51 publications

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“…However, subsequent isomerization to 9-cis RA is poorly understood (45). In addition, CYP26, which is responsible for the breakdown of RA and, hence, deactivation of RAR or RXR, was found to be expressed in the brain of early embryos (46)(47)(48). CYP26 expression may explain the lack of gRXR activation in the brain and the inability of exogenous retinoic acid isomers to induce reporter gene expression anterior to the spinal cord, whereas the synthetic ligand LG268 is able to do so.…”

Section: Discussionmentioning

confidence: 99%

Spatiotemporal retinoid-X receptor activation detected in live vertebrate embryos

Luria

Furlow

2004

Proc. Natl. Acad. Sci. U.S.A.

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Most studies on the nuclear retinoid-X receptor (RXR) have focused on its role as a heterodimeric partner but less about its own activation pattern during development and the distribution of potential endogenous ligands. The aim of this study is to visualize the distribution of activated RXR␣ in live transgenic Xenopus laevis embryos across a wide range of developmental stages. We adopted a nuclear receptor-Gal4 fusion͞upstream activation sequence-based reporter system for our assay. Strong activation of the RXR␣ ligand-binding domain was observed in a segment of the spinal cord just posterior to the hindbrain. This activation is first detected in neurula stage embryos and persists up to swimming tadpole stages, after which activation strongly declines. Addition of exogenous ligands, such as 9-cis retinoic acid or all-trans retinoic acid, expands the activation of RXR throughout the spinal cord but not in the brain, whereas the RXR-specific ligand LG268 expanded the Gal4 -RXR activation into the brain and olfactory epithelia. Treatment with the RAR-specific ligand 4-(E-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid or thyroid hormone had no effect on Gal4 -RXR activation, whereas these compounds significantly increased their corresponding Gal4͞ receptor fusion proteins under similar conditions. Embryos expressing a Gal4 -RXR fusion protein with a deletion in the liganddependent activation domain (AF2) show no reporter gene activation. The results shown in this paper reveal a specific activation pattern for Gal4 -RXR␣ specifically in the developing spinal cord and suggest the existence of RXR ligand ''hot-spots'' in this region.Gal4 ͉ transgenesis ͉ Xenopus laevis ͉ nuclear receptor

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Section: Discussionmentioning

confidence: 99%

Spatiotemporal retinoid-X receptor activation detected in live vertebrate embryos

Luria

Furlow

2004

Proc. Natl. Acad. Sci. U.S.A.

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“…RALDH-2-expressing tissues have been shown to contain retinoid activity as measured by both retinoid-responsive reporter gene activity and direct measurement of RA levels from tissue extracts; by similar analyses, P450RAI-1-expressing tissues do not (7,8). In addition, overexpression of P450RAI-1 in Xenopus embryos has been shown to abrogate the teratogenic effects of exogenously applied RA, consistent with a catabolic role for this enzyme (15). In this report we describe the cloning and characterization of a second all-trans-RA-inducible, all-trans-RA-metabolizing cytochrome P450, P450RAI-2, which is predominantly expressed in brain, cerebellum in particular.…”

mentioning

confidence: 86%

“…tory feedback-loop plays an important role in balancing alltrans-RA levels in certain developing tissues (6,(10)(11)(12)15).…”

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confidence: 99%

Identification of the human cytochrome P450, P450RAI-2, which is predominantly expressed in the adult cerebellum and is responsible for all-trans-retinoic acid metabolism

White

Ramshaw²,

Taimi³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

219

183

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Retinoids, particularly all-trans-retinoic acid (RA), are potent regulators of cell differentiation, cell proliferation, and apoptosis. The role of all-trans-RA during development and in the maintenance of adult tissues has been well established. The control of all-trans-RA levels in cells and tissues is regulated by the balance between its biosynthesis and its catabolism to inactive metabolites. The cytochrome P450 enzyme P450RAI (herein renamed P450RAI-1) is partially responsible for this inactivation of all-trans-RA. In this report, we describe the identification, molecular cloning, and characterization of a second related enzyme, P450RAI-2, which is also involved in the specific inactivation of all-trans-RA. Transiently transfected P450RAI-2 can convert all-trans-RA to more polar metabolites including 4-oxo-, 4-OH-, and 18-OH-all-trans-RA. Competition experiments with other retinoids suggest that all-trans-RA is the preferred substrate. The high level of expression of P450RAI-2, particularly in the cerebellum and pons of human adult brain, suggests a unique role for this enzyme in the protection of specific tissues from exposure to retinoids.

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“…The first member of the CYP26 family to be identified, Cyp26A1, has been described in the Xenopus, chick, and mouse embryo (Fujii et al, 1997;Hollemann et al, 1998;de Roos et al, 1999;Swindell et al, 1999;Blentic et al, 2003). It has a dynamic expression pattern in the anterior epiblast, the tail bud, and the dorsal neural tube.…”

Section: Introductionmentioning

confidence: 99%

Generating gradients of retinoic acid in the chick embryo: Cyp26C1 expression and a comparative analysis of the Cyp26 enzymes

Reijntjes

Gale

Maden

2004

Developmental Dynamics

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We have cloned a novel retinoic acid (RA) catabolizing enzyme, Cyp26C1, in the chick and describe here its distribution during early stages of chick embryogenesis. It is expressed from stage 4 in the presumptive anterior (cephalic) mesoderm, in a subset of cephalic neural crest cells, the ventral otic vesicle, mesenchyme adjacent to the otic vesicle, the branchial pouches and grooves, a part of the neural retina, and the anterior telencephalon, and shows a dynamic expression in the hindbrain rhombomeres and neuronal populations within them. By examining the distribution of Cyp26C1 in the RA-free quail embryo, we can determine which of these expression domains is dependent on RA, and it is only the rhombomeric sites that do not appear, suggesting a role for RA in this location. The most striking domain of Cyp26C1 distribution is in the anterior cephalic mesoderm, which is adjacent to the domain of Raldh2 in the trunk mesoderm, but separated from it by a gap dorsal to which the posterior hindbrain will develop. We suggest that a gradient of RA within the mesoderm generated by Raldh2 and catabolized by Cyp26C1 could be responsible for patterning the hindbrain. We have compared this distribution of Cyp26C1 with that of Cyp26A1 and Cyp26B1 in the chick and shown that they generally occupy nonoverlapping sites of expression in the embryo, and as a result, we suggest individual roles for each of the Cyp enzymes in the developing embryo.

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Regionalized metabolic activity establishes boundaries of retinoic acid signalling

Cited by 156 publications

References 51 publications

Spatiotemporal retinoid-X receptor activation detected in live vertebrate embryos

Spatiotemporal retinoid-X receptor activation detected in live vertebrate embryos

Identification of the human cytochrome P450, P450RAI-2, which is predominantly expressed in the adult cerebellum and is responsible for all-trans-retinoic acid metabolism

Generating gradients of retinoic acid in the chick embryo: Cyp26C1 expression and a comparative analysis of the Cyp26 enzymes

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