Cytochrome P450 Cyp26a1 Alters Spinal Motor Neuron Subtype Identity in Differentiating Embryonic Stem Cells

Ricard, Megan J.; Gudas, Lorraine J.

doi:10.1074/jbc.m113.474254

Cited by 10 publications

(6 citation statements)

References 69 publications

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“…Cyp26a1 is responsible for metabolizing RA into its polar metabolites, 4‐oxo‐ and 4‐hydroxy‐RA . Thus, Cyp26a1‐deficient mESCs have higher intracellular concentrations of RA compared to those of their WT counterparts . We observed a 0.5‐fold and a 0.75‐fold decrease in Tcf1 transcript levels in WT and Cyp26a1 − / − mESCs, respectively (Fig.…”

Section: Resultsmentioning

confidence: 69%

Retinoic Acid Suppresses the Canonical Wnt Signaling Pathway in Embryonic Stem Cells and Activates the Noncanonical Wnt Signaling Pathway

Osei-Sarfo

Gudas

2014

Stem Cells

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Embryonic stem cells (ESCs) have both the ability to self-renew and to differentiate into various cell lineages. Retinoic acid (RA), a metabolite of Vitamin A, has a critical function in initiating lineage differentiation of ESCs through binding to the retinoic acid receptors (RARs). Additionally, the Wnt signaling pathway plays a role in pluripotency and differentiation, depending on the activation status of the canonical and noncanonical pathways. The activation of the canonical Wnt signaling pathway, which requires the nuclear accumulation of β-catenin and its interaction with Tcf1/Lef at Wnt response elements, is involved in ESC stemness maintenance. The noncanonical Wnt signaling pathway, through actions of Tcf3, can antagonize the canonical pathway. We show that RA activates the noncanonical Wnt signaling pathway, while concomitantly inhibiting the canonical pathway. RA increases the expression of ligands and receptors of the noncanonical Wnt pathway (Wnt 5a, 7a, Fzd2 and Fzd6), downstream signaling, and Tcf3 expression. RA reduces the phosphorylated β-catenin level by 4-fold, though total β-catenin levels don't change. We show that RA signaling increases the dissociation of Tcf1 and the association of Tcf3 at promoters of genes that regulate stemness (e.g. NR5A2,Lrh-1) or differentiation (eg. Cyr61, Zic5). Knockdown of Tcf3 increases Lrh-1 transcript levels in mESCs and prevents the RA-associated, ∼4-fold increase in Zic5, indicating that RA requires Tcf3 to effect changes in Zic5 levels. We demonstrate a novel role for RA in altering the activation of these two Wnt signaling pathways and show that Tcf3 mediates some actions of RA during differentiation.

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Section: Resultsmentioning

confidence: 69%

Retinoic Acid Suppresses the Canonical Wnt Signaling Pathway in Embryonic Stem Cells and Activates the Noncanonical Wnt Signaling Pathway

Osei-Sarfo

Gudas

2014

Stem Cells

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“…The CYP26 family genes were significantly repressed by all trans-retinoic acid (ATRA) and kept at a low level during neural differentiation (Xi and Yang, 2008). Overexpression of CYP26A1 induces neurodegenerative diseases by enhancing retinoic acid (RA) metabolites (Ricard and Gudas, 2013). Cationic PAMAM induced the expression of CYP26A1, which is considered to be a potential risk for neural toxicity in the human brain.…”

Section: A B C Dmentioning

confidence: 99%

Effects of PAMAM dendrimers with various surface functional groups and multiple generations on cytotoxicity and neuronal differentiation using human neural progenitor cells

et al. 2016

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-Polyamidoamine (PAMAM) dendrimers have potential for biological applications as delivery systems for genes, drugs, and imaging agents into the brain, but their developmental neurotoxicity remains unknown. We investigated the effects of PAMAM dendrimers with various surface functional groups and multiple generations on neuronal differentiation using human neural progenitor cells at an equal mass concentration. Only PAMAM dendrimers containing amine (NH 2 ) surface groups at concentrations of 10 μg/mL significantly reduced cell viability and neuronal differentiation, compared with non-amine-terminated dendrimers. PAMAM-NH 2 with generation (G)3, G4, G5 G6, and G7 significantly decreased cell viability and inhibited neuronal differentiation from a concentration of 5 μg/mL, but G0, G1, and G2 dendrimers did not have any effect at this concentration. Cytotoxicity indices of PAMAM-NH 2 dendrimers at 10 μg/mL correlated well with the zeta potentials of the particles. Surface group density and particle number in unit volume is more important characteristic than particle size to influence cytotoxicity for positive changed dendrimers. PAMAM-50% C 12 at 1 μg/mL altered the expression level of the oxidative stress-related genes, ROR1, CYP26A1, and TGFB1, which is a DNA damage response gene. Our results indicate that PAMAM dendrimer exposure may have a surface charge-dependent adverse effect on neuronal differentiation, and that the effect may be associated with oxidative stress and DNA damage during development of neural cells.

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“…All-transretinoic acid (RA) 2 is a metabolite of vitamin A (retinol) and functions as a potent inducer of stem cell differentiation (1,2). We and others have shown that RA can induce differentiation of both human and murine ES cells into various specified lineages (3)(4)(5)(6)(7)(8)(9)(10). The extensive cell culture applications of RA are reflections of the plethora of developmental processes in which RA is involved (11)(12)(13)(14)(15)(16).…”

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confidence: 99%

Combinatorial knockout of RARα, RARβ, and RARγ completely abrogates transcriptional responses to retinoic acid in murine embryonic stem cells

Laursen

Gudas

2018

Journal of Biological Chemistry

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All--retinoic acid (RA), a potent inducer of cellular differentiation, functions as a ligand for retinoic acid receptors (RARα, β, and γ). RARs are activated by ligand binding, which induces transcription of direct genomic targets. However, whether embryonic stem cells respond to RA through routes that do not involve RARs is unknown. Here, we used CRISPR technology to introduce biallelic frameshift mutations in RARα, RARβ, and RARγ, thereby abrogating all RAR functions in murine embryonic stem cells. We then evaluated RA-responsiveness of the RAR-null cells using RNA-Seq transcriptome analysis. We found that the RAR-null cells display no changes in transcripts in response to RA, demonstrating that the RARs are essential for the regulation of all transcripts in murine embryonic stem cells in response to RA. Our key finding, that in embryonic stem cells the transcriptional effects of RA all depend on RARs, addresses a long-standing topic of discussion in the field of retinoic acid signaling.

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Cytochrome P450 Cyp26a1 Alters Spinal Motor Neuron Subtype Identity in Differentiating Embryonic Stem Cells

Cited by 10 publications

References 69 publications

Retinoic Acid Suppresses the Canonical Wnt Signaling Pathway in Embryonic Stem Cells and Activates the Noncanonical Wnt Signaling Pathway

Retinoic Acid Suppresses the Canonical Wnt Signaling Pathway in Embryonic Stem Cells and Activates the Noncanonical Wnt Signaling Pathway

Effects of PAMAM dendrimers with various surface functional groups and multiple generations on cytotoxicity and neuronal differentiation using human neural progenitor cells

Combinatorial knockout of RARα, RARβ, and RARγ completely abrogates transcriptional responses to retinoic acid in murine embryonic stem cells

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