The role of CYP26 enzymes in defining appropriate retinoic acid exposure during embryogenesis

Pennimpede, Tracie; Cameron, Don; MacLean, Glenn; Li, Hui; Abu-Abed, Suzan; Petkovich, Martin

doi:10.1002/bdra.20709

Cited by 130 publications

(128 citation statements)

References 127 publications

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“…Unlike the other two enzymes, CYP26C1 prefers 9-cis -RA as substrate and exhibits broader substrate specifi city in general. Furthermore, CYP26C1 shows a different response to treatment with atRA and 9-cis -RA, being upregulated in some tissues and cells but downregulated in others ( 129 ). Of the three CYP26 genes, CYP26C1 is the least conserved, and its physiological function remains poorly understood.…”

Section: Biosynthesis Of Atra From ␤ -Carotenementioning

confidence: 99%

Enzymology of retinoic acid biosynthesis and degradation

Kedishvili

2013

Journal of Lipid Research

170

165

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This article is available online at http://www.jlr.org ( 10 ), and regulation of energy homeostasis ( 11,12 ). atRA exerts its actions by serving as an activating ligand of nuclear atRA receptors [retinoid acid receptor (RAR) ␣ , RAR ␤ , and RAR ␥ ] and peroxisome proliferator-activated receptors (PPAR) ␤ / ␦ , which form heterodimers with retinoid X receptors ( 13,14 ). The actions of the RARs are described in more detail in this thematic series by RochetteEgly and colleagues. The concentration of atRA during embryonic development is tightly controlled in a spatial and temporal manner, and in adult tissues, it is maintained within a very narrow range that is specifi c for each given tissue. If the control mechanisms fail and the concentration of atRA exceeds or falls below the optimal range, tissues and cells undergo pathophysiological changes that in most severe cases can lead to disease. Thus, the maintenance of optimal atRA levels is essential for life. This review focusses on recent fi ndings regarding the mechanisms that control atRA homeostasis, with specifi c emphasis on the enzymes involved in atRA biosynthesis and degradation. All-trans -retinoic acid (atRA) is a highly potent derivative of vitamin A that is required for virtually all essential physiological processes and functions because of its involvement in transcriptional regulation of over 530 different genes ( 1, 2 ). For example, atRA is necessary for differentiation and development of fetal and adult tissues, stem cell differentiation, and apoptosis ( 3-7 ), and for support of reproductive functions ( 8, 9 ), immune response

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Section: Biosynthesis Of Atra From ␤ -Carotenementioning

confidence: 99%

Enzymology of retinoic acid biosynthesis and degradation

Kedishvili

2013

Journal of Lipid Research

170

165

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“…The amount of RA to which a particular cell or tissue is exposed is tightly regulated, being controlled at multiple levels (reviewed by (Niederreither and Dolle 2008;Pennimpede et al, 2010)). First, the availability of retinol during embryonic development is dependent on the mother's diet.…”

Section: Fine-tuning Retinoid Levels: Synthesis Vs Degradationmentioning

confidence: 99%

Regulation of germ cell meiosis in the fetal ovary

Spiller¹,

Bowles²,

Koopman³

2012

Int. J. Dev. Biol.

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Fertility depends on correct regulation of meiosis, the special form of cell division that gives rise to haploid gametes. In female mammals, germ cells enter meiosis during fetal ovarian development, while germ cells in males avoid entering meiosis until puberty. Decades of research have shown that meiotic entry, and germ cell sex determination, are not initiated intrinsically within the germ cells. Instead, meiosis is induced by signals produced by the surrounding somatic cells. More recently, retinoic acid (RA), the active derivative of vitamin A, has been implicated in meiotic induction during fetal XX and postnatal XY germ cell development. Evidence for an intricate system of RA synthesis and degradation in the fetal ovary and testis has emerged, explaining past observations of infertility in vitamin A-deficient rodents. Here we review how meiosis is triggered in fetal ovarian germ cells, paying special attention to the role of RA in this process.

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“…Moreover, in the developing limb bud, Aldh1a2 appears to be the predominant RA synthesis enzyme because Aldh1a2-null animals present with a wide spectrum of defects, including severe limb abnormalities, whereas loss of Aldh1a1 or Aldh1a3 has a more limited impact on development (Niederreither and Dolle, 2008). CYP26 enzymes serve to catabolise all-trans RA (at-RA) into more polar inactive metabolites that appear to have negligible RAR transcriptional activity (Pennimpede et al, 2010a). Both Cyp26a1 and Cyp26b1 are expressed in the developing skeleton, and appear in mesenchymal condensations, and subsequently in differentiating chondroblasts and osteoblasts (de Roos et al, 1999;Laue et al, 2008;Maclean et al, 2009;Spoorendonk et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Genetic deletion of Cyp26b1 negatively impacts limb skeletogenesis by inhibiting chondrogenesis

et al. 2011

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SummaryCyp26b1, a retinoic acid (RA)-metabolising enzyme, is expressed in the developing limb bud, and Cyp26b1 -/-mice present with severe limb defects. These malformations might be attributable to an RA-induced patterning defect; however, recent reports suggest that RA is dispensable for limb patterning. In this study, we examined the role of endogenous retinoid signalling in skeletogenesis using Cyp26b1 -/-mice and transgenic mice in which Cyp26b1 is conditionally deleted under control of the Prrx1 promoter beginning at E9.5 (Prrx1Cre + /Cyp26b1 fl/fl ). We found that the limb phenotype in Prrx1Cre + /Cyp26b1 fl/fl mice was less severe than that observed in Cyp26b1 -/-animals and that a change in retinoid signalling contributed to the difference in phenotypes. We systematically examined the role of endogenous RA signalling in chondrogenesis and found that Cyp26b1 -/-cells and limb mesenchymal cells treated with a CYP inhibitor, are maintained in a pre-chondrogenic state, exhibit reduced chondroblast differentiation and have modestly accelerated chondrocyte hypertrophy. Furthermore, Cyp26b1 -/-mesenchyme exhibited an increase in expression of genes in a closely related tendogenic lineage, indicating that retinoid signals in the limb interfere with differentiation and maintain progenitor status. Together, these findings support an important function for RA in regulating the behaviour of mesenchymal progenitors, and their subsequent differentiation and maturation.

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The role of CYP26 enzymes in defining appropriate retinoic acid exposure during embryogenesis

Cited by 130 publications

References 127 publications

Enzymology of retinoic acid biosynthesis and degradation

Enzymology of retinoic acid biosynthesis and degradation

Regulation of germ cell meiosis in the fetal ovary

Genetic deletion of Cyp26b1 negatively impacts limb skeletogenesis by inhibiting chondrogenesis

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