Input overload: Contributions of retinoic acid signaling feedback mechanisms to heart development and teratogenesis

D’Aniello, Enrico; Waxman, Joshua S.

doi:10.1002/dvdy.24232

Cited by 36 publications

(51 citation statements)

References 135 publications

(254 reference statements)

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“…Because RA production is maintained in homeostatic balance via feedback regulation (D’Aniello and Waxman, 2015; Sandell et al, 2012), and because of the reversible nature of the Retinol/Retinal conversion reaction, supplementation with atRAL at these dosage levels does not markedly disturb normal RA signaling in wild type embryos (Fig. 2 A–C).…”

Section: Resultsmentioning

confidence: 99%

“…6 C and 3 E), we do not know if the RA is present the cultured glands accurately reflects the RA signaling pattern that occurs in vivo. In vivo , disturbances of RA signaling levels are buffered by feedback regulation of RA production, RA signaling, and RA degradation, and can yield paradoxical consequences in RA regulation (D’Aniello et al, 2013; D’Aniello and Waxman, 2015; Lee et al, 2012; Sandell et al, 2012). Thus, it is possible that cultured glands, lacking the Vitamin A precursor normally available in circulating serum, experience feedback regulatory changes in RA homeostasis relative to glands in vivo , possibly increasing transcription of RAR receptors or decreasing transcription of RA degrading enzymes.…”

Section: Discussionmentioning

confidence: 99%

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Retinoic acid regulates embryonic development of mammalian submandibular salivary glands

Wright

Buenger

Abashev

et al. 2015

Developmental Biology

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Organogenesis is orchestrated by cell and tissue interactions mediated by molecular signals. Identification of relevant signals, and the tissues that generate and receive them, are important goals of developmental research. Here, we demonstrate that Retinoic Acid (RA) is a critical signaling molecule important for morphogenesis of mammalian submandibular salivary glands (SMG). By examining late stage RA deficient embryos of Rdh10 mutant mice we show that SMG development requires RA in a dose-dependent manner. Additionally, we find that active RA signaling occurs in SMG tissues, arising earlier than any other known marker of SMG development and persisting throughout gland morphogenesis. At the initial bud stage of development, we find RA production occurs in SMG mesenchyme, while RA signaling occurs in epithelium. We also demonstrate active RA signaling occurs in glands cultured ex vivo, and treatment with an inhibitor of RA signaling blocks growth and branching. Together these data identify RA signaling as a direct regulator of SMG organogenesis.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Retinoic acid regulates embryonic development of mammalian submandibular salivary glands

Wright

Buenger

Abashev

et al. 2015

Developmental Biology

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“…This is attested foremost by the fact that Cyp26 enzymes were first identified in studies investigating genes upregulated upon RA exposure in mouse embryonic stem (ES) cells and zebrafish embryos (Ray et al, ; White et al, ). The administration of exogenous RA to developing embryos was shown to upregulate the expression and spatial domains of Cyp26 enzymes in Xenopus , zebrafish, and Ciona , often with a concomitant downregulation of RA synthesis enzymes (D'Aniello & Waxman, ; Dobbs‐McAuliffe, Zhao, & Linney, ; Ishibashi et al, ; Tanibe et al, ). Indeed, studies in zebrafish embryos demonstrated that the ability of RA to induce the expression of Cyp26 enzymes is the mechanism behind prolonged loss of RA after a teratogenic insult.…”

Section: Cyp26‐mediated Ra Gradients Formation and Regulationmentioning

confidence: 99%

Generating retinoic acid gradients by local degradation during craniofacial development: One cell's cue is another cell's poison

Dubey

Rose

Jones

et al. 2018

Genesis

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Retinoic acid (RA) is a vital morphogen for early patterning and organogenesis in the developing embryo. RA is a diffusible, lipophilic molecule that signals via nuclear RA receptor heterodimeric units that regulate gene expression by interacting with RA response elements in promoters of a significant number of genes. For precise RA signaling, a robust gradient of the morphogen is required. The developing embryo contains regions that produce RA, and specific intracellular concentrations of RA are created through local degradation mediated by Cyp26 enzymes. In order to elucidate the mechanisms by which RA executes precise developmental programs, the kinetics of RA metabolism must be clearly understood. Recent advances in techniques for endogenous RA detection and quantification have paved the way for mechanistic studies to shed light on downstream gene expression regulation coordinated by RA. It is increasingly coming to light that RA signaling operates not only at precise concentrations but also employs mechanisms of degradation and feedback inhibition to self-regulate its levels. A global gradient of RA throughout the embryo is often found concurrently with several local gradients, created by juxtaposed domains of RA synthesis and degradation. The existence of such local gradients has been found especially critical for the proper development of craniofacial structures that arise from the neural crest and the cranial placode populations. In this review, we summarize the current understanding of how local gradients of RA are established in the embryo and their impact on craniofacial development.

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“…Conversely, genes involved in RA catabolism are expressed in regions of the embryo where RA signaling is absent [167,168,169]. Many of the vitamin A metabolic, or catabolic genes are controlled by positive and negative feedback from RA signaling (reviewed in [170]). Genes that are transcriptionally regulated by feedback from RA include those involved in vitamin A metabolism and RA production [104,106,133,134,164].…”

Section: Tissue-specific Gene Expression and Feedback Regulationmentioning

confidence: 99%

Enzymatic Metabolism of Vitamin A in Developing Vertebrate Embryos

Metzler

Sandell

2016

Nutrients

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Embryonic development is orchestrated by a small number of signaling pathways, one of which is the retinoic acid (RA) signaling pathway. Vitamin A is essential for vertebrate embryonic development because it is the molecular precursor of the essential signaling molecule RA. The level and distribution of RA signaling within a developing embryo must be tightly regulated; too much, or too little, or abnormal distribution, all disrupt embryonic development. Precise regulation of RA signaling during embryogenesis is achieved by proteins involved in vitamin A metabolism, retinoid transport, nuclear signaling, and RA catabolism. The reversible first step in conversion of the precursor vitamin A to the active retinoid RA is mediated by retinol dehydrogenase 10 (RDH10) and dehydrogenase/reductase (SDR family) member 3 (DHRS3), two related membrane-bound proteins that functionally activate each other to mediate the interconversion of retinol and retinal. Alcohol dehydrogenase (ADH) enzymes do not contribute to RA production under normal conditions during embryogenesis. Genes involved in vitamin A metabolism and RA catabolism are expressed in tissue-specific patterns and are subject to feedback regulation. Mutations in genes encoding these proteins disrupt morphogenesis of many systems in a developing embryo. Together these observations demonstrate the importance of vitamin A metabolism in regulating RA signaling during embryonic development in vertebrates.

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Input overload: Contributions of retinoic acid signaling feedback mechanisms to heart development and teratogenesis

Cited by 36 publications

References 135 publications

Retinoic acid regulates embryonic development of mammalian submandibular salivary glands

Retinoic acid regulates embryonic development of mammalian submandibular salivary glands

Generating retinoic acid gradients by local degradation during craniofacial development: One cell's cue is another cell's poison

Enzymatic Metabolism of Vitamin A in Developing Vertebrate Embryos

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