Global analysis of RAR‐responsive genes in the <i>Xenopus</i> neurula using cDNA microarrays

Arima, Kayo; Shiotsugu, Jason; Niu, Rong; Khandpur, Ritika; Martinez, Mayra P.; Shin, Yongchol; Koide, Tetsuya; Cho, Ken W.Y.; Kitayama, Atsushi; Ueno, Naoto; Chandraratna, Roshantha A.S.; Blumberg, Bruce

doi:10.1002/dvdy.20231

Cited by 53 publications

(47 citation statements)

References 108 publications

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“…Treatment with the pan-RAR inverse agonist AGN193109 increased the expression of genes involved in patterning anterior neural structures, whereas treatment with pan-RAR agonist TTNPB decreased the expression of anterior marker and cement glandspecific genes (Koide et al, 2001), revealing a set of genes specifically upregulated/downregulated by TTNPB (Arima et al, 2005). Validation studies identified a subset upregulated by AGN193109.…”

Section: Resultsmentioning

confidence: 94%

Active repression by RARγ signaling is required for vertebrate axial elongation

et al. 2014

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Retinoic acid receptor gamma 2 (RARγ2) is the major RAR isoform expressed throughout the caudal axial progenitor domain in vertebrates. During a microarray screen to identify RAR targets, we identified a subset of genes that pattern caudal structures or promote axial elongation and are upregulated by increased RARmediated repression. Previous studies have suggested that RAR is present in the caudal domain, but is quiescent until its activation in late stage embryos terminates axial elongation. By contrast, we show here that RARγ2 is engaged in all stages of axial elongation, not solely as a terminator of axial growth. In the absence of RA, RARγ2 represses transcriptional activity in vivo and maintains the pool of caudal progenitor cells and presomitic mesoderm. In the presence of RA, RARγ2 serves as an activator, facilitating somite differentiation. Treatment with an RARγ-selective inverse agonist (NRX205099) or overexpression of dominant-negative RARγ increases the expression of posterior Hox genes and that of marker genes for presomitic mesoderm and the chordoneural hinge. Conversely, when RAR-mediated repression is reduced by overexpressing a dominant-negative co-repressor (c-SMRT), a constitutively active RAR (VP16-RARγ2), or by treatment with an RARγ-selective agonist (NRX204647), expression of caudal genes is diminished and extension of the body axis is prematurely terminated. Hence, gene repression mediated by the unliganded RARγ2-co-repressor complex constitutes a novel mechanism to regulate and facilitate the correct expression levels and spatial restriction of key genes that maintain the caudal progenitor pool during axial elongation in Xenopus embryos.

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Section: Resultsmentioning

confidence: 94%

Active repression by RARγ signaling is required for vertebrate axial elongation

et al. 2014

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“…Erf was upregulated by increased RA signaling in neurula embryos (Arima et al, 2005). Here, we show that morpholino oligonucleotide (MO)-mediated knockdown of Erf or Etv3 results in loss of primary neurons accompanied by paralysis, phenocopying RAR loss of function.…”

Section: Introductionmentioning

confidence: 83%

“…We have previously shown that some Ets genes were responsive to changes in RAR signaling in Xenopus embryos (Arima et al, 2005). Erf was upregulated by increased RA signaling in neurula embryos (Arima et al, 2005).…”

Section: Introductionmentioning

confidence: 95%

ERF and ETV3L are retinoic acid-inducible repressors required for primary neurogenesis

et al. 2013

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SUMMARYCells in the developing neural tissue demonstrate an exquisite balance between proliferation and differentiation. Retinoic acid (RA) is required for neuronal differentiation by promoting expression of proneural and neurogenic genes. We show that RA acts early in the neurogenic pathway by inhibiting expression of neural progenitor markers Geminin and Foxd4l1, thereby promoting differentiation. Our screen for RA target genes in early Xenopus development identified Ets2 Repressor Factor (Erf) and the closely related ETS repressors Etv3 and Etv3-like (Etv3l). Erf and Etv3l are RA responsive and inhibit the action of ETS genes downstream of FGF signaling, placing them at the intersection of RA and growth factor signaling. We hypothesized that RA regulates primary neurogenesis by inducing Erf and Etv3l to antagonize proliferative signals. Loss-of-function analysis showed that Erf and Etv3l are required to inhibit proliferation of neural progenitors to allow differentiation, whereas overexpression of Erf led to an increase in the number of primary neurons. Therefore, these RA-induced ETS repressors are key components of the proliferation-differentiation switch during primary neurogenesis in vivo.

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“…HoxA1-null ES cells are refractory to treatment with RA as measured by reduced expression of post-mitotic neuron markers (e.g., b-tubulin III, Nestin); RA sensitivity can be restored by rescue with HoxA1 cDNA [173]. Btg2 is also a putative direct target of RAR [174] and is induced by RA in neurula-stage embryos [175,176] and in various cell lines [174,177]. Btg2 decreases arginine methylation and lysine acetylation of histone H4 at RAR target genes, thus increasing the transcriptional activity of RAR [177].…”

Section: Downstream Effectors Of Retinoic Acid Signaling Related To Nmentioning

confidence: 99%

“…Multiple genomics-based studies have elucidated some genes that respond to RA under a variety of differentiation conditions [175,176,[190][191][192][193][194][195][196]. A subset of the genes identified in these analyses will be candidate neurogenic genes regulated by RAR.…”

Section: Downstream Effectors Of Retinoic Acid Signaling Related To Nmentioning

confidence: 99%