Homozygous deletion of the CRABPI gene in AB1 embryonic stem cells results in increased CRABPII gene expression and decreased intracellular retinoic acid concentration

Chen, Anne C.; Yu, Ker; Lane, Michelle A.; Gudas, Lorraine J.

doi:10.1016/s0003-9861(02)00732-4

Cited by 28 publications

(18 citation statements)

References 92 publications

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“…Crabps facilitate interactions between RA and RARs in vitro (Aström et al, 1991;Delva et al, 1999;Budhu and Noy, 2002), but also bind RA in the cytosol preventing its entry into the nucleus and promoting degradation (Boylan and Gudas, 1991;Boylan and Gudas, 1992;Fiorella and Napoli, 1994;Chen et al, 2003). Consistent with previous studies (Sharma et al, 2005) of the four zebrafish Crabps (crabp1a,crabp1b,crabp2a,crabp2b), all but crabp1a were detected during gastrulation (6-9 hpf; supplementary material Figs S1, S2).…”

Section: Results and Discussion A Novel Requirement For Crabps In Hoxsupporting

confidence: 82%

Cellular retinoic acid-binding proteins are essential for hindbrain patterning and signal robustness in zebrafish

et al. 2012

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SUMMARYThe vitamin A derivative retinoic acid (RA) is a morphogen that patterns the anterior-posterior axis of the vertebrate hindbrain. Cellular retinoic acid-binding proteins (Crabps) transport RA within cells to both its nuclear receptors (RARs) and degrading enzymes (Cyp26s). However, mice lacking Crabps are viable, suggesting that Crabp functions are redundant with those of other fatty acid-binding proteins. Here we show that Crabps in zebrafish are essential for posterior patterning of the hindbrain and that they provide a key feedback mechanism that makes signaling robust as they are able to compensate for changes in RA production. Of the four zebrafish Crabps, Crabp2a is uniquely RA inducible and depletion or overexpression of Crabp2a makes embryos hypersensitive to exogenous RA. Computational models confirm that Crabp2a improves robustness within a narrow concentration range that optimizes a 'robustness index', integrating spatial information along the RA morphogen gradient. Exploration of signaling parameters in our models suggests that the ability of Crabp2a to transport RA to Cyp26 enzymes for degradation is a major factor in promoting robustness. These results demonstrate a previously unrecognized requirement for Crabps in RA signaling and hindbrain development, as well as a novel mechanism for stabilizing morphogen gradients despite genetic or environmental fluctuations in morphogen availability.

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Section: Results and Discussion A Novel Requirement For Crabps In Hoxsupporting

confidence: 82%

Cellular retinoic acid-binding proteins are essential for hindbrain patterning and signal robustness in zebrafish

et al. 2012

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“…Zebrafish possess two CRABPs (CRABP I and CRABP II) and these genes are expressed in various tissues reliant on RA signaling during zebrafish embryogenesis, including the central nervous system and retina Sharma et al, 2005). Deletion of crabp1 in murine embryonic stem cells caused intracellular RA levels to decrease, indicating the mediation effects of CRABP I on RA homeostasis in cells (Chen et al, 2003). Therefore, significant down-regulation of crabp1a and crabp2a would result in less RA being transported to the nucleus and this would interfere with RA signaling.…”

Section: Discussionmentioning

confidence: 99%

Effects of acute exposure to polybrominated diphenyl ethers on retinoid signaling in zebrafish larvae

Chen

et al. 2013

Environmental Toxicology and Pharmacology

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“…It has been suggested that CRABP I over-expression may increase initial intracellular RA concentrations (Chen et al, 2003). Furthermore, over-expression of CRABP I can enhance the RA induction of a reporter construct and cyclin D1 expression (Wei et al, 1999;Blaese et al, 2003), while antisense oligonucleotides to CRABP I partially inhibited the RA-induced expression of TGFb, RARb and tenascin (Nugent and Greene, 1995).…”

Section: Discussionmentioning

confidence: 99%

Increasing the intracellular availability of all-trans retinoic acid in neuroblastoma cells

et al. 2005

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Recent data indicate that isomerisation to all- trans retinoic acid (ATRA) is the key mechanism underlying the favourable clinical properties of 13- cis retinoic acid (13cisRA) in the treatment of neuroblastoma. Retinoic acid (RA) metabolism is thought to contribute to resistance, and strategies to modulate this may increase the clinical efficacy of 13cisRA. The aim of this study was to test the hypothesis that retinoids, such as acitretin, which bind preferentially to cellular retinoic acid binding proteins (CRABPs), or specific inhibitors of the RA hydroxylase CYP26, such as R116010, can increase the intracellular availability of ATRA. Incubation of SH-SY5Y cells with acitretin (50 μ M ) or R116010 (1 or 10 μ M ) in combination with either 10 μ M ATRA or 13cisRA induced a selective increase in intracellular levels of ATRA, while 13cisRA levels were unaffected. CRABP was induced in SH-SY5Y cells in response to RA. In contrast, acitretin had no significant effect on intracellular retinoid concentrations in those neuroblastoma cell lines that showed little or no induction of CRABP after RA treatment. Both ATRA and 13cisRA dramatically induced the expression of CYP26A1 in SH-SY5Y cells, and treatment with R116010, but not acitretin, potentiated the RA-induced expression of a reporter gene and CYP26A1. The response of neuroblastoma cells to R116010 was consistent with inhibition of CYP26, indicating that inhibition of RA metabolism may further optimise retinoid treatment in neuroblastoma.

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Homozygous deletion of the CRABPI gene in AB1 embryonic stem cells results in increased CRABPII gene expression and decreased intracellular retinoic acid concentration

Cited by 28 publications

References 92 publications

Cellular retinoic acid-binding proteins are essential for hindbrain patterning and signal robustness in zebrafish

Cellular retinoic acid-binding proteins are essential for hindbrain patterning and signal robustness in zebrafish

Effects of acute exposure to polybrominated diphenyl ethers on retinoid signaling in zebrafish larvae

Increasing the intracellular availability of all-trans retinoic acid in neuroblastoma cells

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