A conserved retinoic acid response element required for early expression of the homeobox gene Hoxb-1

Marshall, Heather; Studer, Michèle; Pöpperl, Heike; Aparicio, Samuel; Kuroiwa, Atsushi; Brenner, Sydney; Krumlauf, Robb

doi:10.1038/370567a0

Cited by 431 publications

(266 citation statements)

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“…These characteristics led to the original proposal to sequence the Fugu genome in order to assist with the annotation of human genes based on comparative genomics [10]. Furthermore, the availability of Fugu genomic sequence also revealed that human-Fugu conserved noncoding sequences can be used to delineate gene regulatory sequences [1,[11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

In vivo characterization of a vertebrate ultraconserved enhancer

et al. 2005

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Genomic sequence comparisons between human, mouse and pufferfish (Takifugu rubripes (Fugu)) have revealed a set of extremely conserved noncoding sequences. While this high degree of sequence conservation suggests severe evolutionary constraint and predicts a lack of tolerance to change in order to retain in vivo functionality, such elements have been minimally explored experimentally. In this study, we describe the in-depth characterization of an ancient conserved enhancer, Dc2 located near the dachshund gene, which displays a human-Fugu identity of 84% over 424 basepairs (bp). In addition to this large overall conservation, we find that Dc2 is characterized by the presence of a large block of sequence (144 bp) that is completely identical between human, mouse, chicken, zebrafish and Fugu. Through the testing of reporter vector constructs in transgenic mice, we observed that the 424 bp Dc2 conserved element is necessary and sufficient for brain tissue enhancer activity. In vivo analyses also revealed that the 144 bp 100% conserved sequence is necessary, but not sufficient, to replicate Dc2 enhancer function. However, the introduction of two separate 16 bp insertions into the highly conserved enhancer core did not cause any detectable modification of its in vivo activity. Our observations indicate that the 144 bp 100% conserved element is tolerant of change at least at the resolution of this transgenic mouse assay and suggest that purifying selection on Dc2 sequence might not be as strong as we predicted or that some unknown property also constrains this highly conserved enhancer sequence. Thank you for your letter of February 15 th and for the reviewers' comments on our manuscript entitled "In Vivo Characterization of a Vertebrate Ultra-conserved Enhancer", by Poulin et al. We have addressed the reviewers' concerns in a revised manuscript, which we are resubmitting for your consideration.Our detailed response is as follows:Reviewer #21. Abstract -last sentence should read: "tolerant of change at least AT the resolution…"We have changed this typo. 2.Introduction paragraph four (page 4), first sentence. Statement "which is involved in embryonic development" is too vague. Please state, briefly, the function of DACH.We have added an introduction description of DACHs known function and reference to its Drosophila homolog. 3.Introduction paragraph four (page 4). When first introducing Dc2, please define it as a conserved, functional element at DACH (i.e., since the Dc nomenclature was not used previously in the text).We have made this change. 4.Introduction paragraph four (page 4). Please provide a reference for the statement "known degeneracy of the sequences recognized by transcription factors".We have added a reference. 5.Results paragraph one (page 5), first sentence. Please restate the locus (DACH) at which Dc2 resides.We have made this change. 6.Results "Refinement of the Minimal Necessary Dc2 Enhancer". Authors state that the 424 bp fragment drives expression pattern in transgenics that is "indistingu...

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Section: Introductionmentioning

confidence: 99%

In vivo characterization of a vertebrate ultraconserved enhancer

et al. 2005

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“…The Role of RA Receptors and Prep1 in Actin-dependent HoxB Induction by RA Because RARs are important in HoxB expression in the neural region (Marshall et al, 1994(Marshall et al, , 1996Gould et al, 1998), we tested whether treatment with CytD affected the expression of any of these receptors. As shown in Table 3, CytD did not affect the expression levels of any of the RAR and retinoid X receptor (RXR) transcription factors, either in the absence or in the presence of RA.…”

Section: N-wasp Down-regulation Inhibits the Expression Of The Hoxb Cmentioning

confidence: 99%

“…Cell fate-determining clustered Hox genes are expressed colinearly in the same order as their location on the genome, generating anteriorto-posterior identities (Krumlauf, 1994). Several lines of evidence have demonstrated the importance of RA receptors (RARs) for patterning and basal expression of Hox genes in the vertebrate neural tube (Marshall et al, 1994(Marshall et al, , 1996Gould et al, 1998;Dupe et al, 1999). However, expression of anterior HoxB genes also depends on an auto-regulatory circuit involving the HoxB1 protein and the Prep1-Pbx1 complex (Marshall et al, 1996;Maconochie et al, 1997;Dupe et al, 1999;Jacobs et al, 1999;Ryoo et al, 1999;Ferretti et al, 2000Ferretti et al, , 2005Huang et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Induction of HoxB Transcription by Retinoic Acid Requires Actin Polymerization

Ferrai

Naum-Onganía

Longobardi

et al. 2009

MBoC

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We have analyzed the role of actin polymerization in retinoic acid (RA)-induced HoxB transcription, which is mediated by the HoxB regulator Prep1. RA induction of the HoxB genes can be prevented by the inhibition of actin polymerization. Importantly, inhibition of actin polymerization specifically affects the transcription of inducible Hox genes, but not that of their transcriptional regulators, the RARs, nor of constitutively expressed, nor of actively transcribed Hox genes. RA treatment induces the recruitment to the HoxB2 gene enhancer of a complex composed of "elongating" RNAPII, Prep1, ␤-actin, and N-WASP as well as the accessory splicing components p54Nrb and PSF. We show that inhibition of actin polymerization prevents such recruitment. We conclude that inducible Hox genes are selectively sensitive to the inhibition of actin polymerization and that actin polymerization is required for the assembly of a transcription complex on the regulatory region of the Hox genes.

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“…RA directly regulates gene expression through its nuclear hormone receptor (RAR) and co-receptor (RXR), which bind RA response elements (RAREs) in the enhancers of target genes (Bastien and Rochette-Egly, 2004). In the hindbrain, RA regulates the expression of 3Ј-Hox genes through direct (in the case of Hox-1 and Hox-4 genes) or indirect (in the case of Hox-3 genes) mechanisms (Gould et al, 1998;Hernandez et al, 2004;Marshall et al, 1994;Nolte et al, 2003;Studer et al, 1994;Zhang et al, 2000). Other anterior RAresponsive genes (Hox-1 family genes) are expressed earlier and at lower RA concentrations than the more-posterior RA-responsive genes (Hox-4 family genes) (Dupe and Lumsden, 2001;Maves and Kimmel, 2005;Simeone et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Cyp26 enzymes generate the retinoic acid response pattern necessary for hindbrain development

et al. 2007

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Retinoic acid (RA) is essential for normal vertebrate development,including the patterning of the central nervous system. During early embryogenesis, RA is produced in the trunk mesoderm through the metabolism of vitamin A derived from the maternal diet and behaves as a morphogen in the developing hindbrain where it specifies nested domains of Hox gene expression. The loss of endogenous sources of RA can be rescued by treatment with a uniform concentration of exogenous RA, indicating that domains of RA responsiveness can be shaped by mechanisms other than the simple diffusion of RA from a localized posterior source. Here, we show that the cytochrome p450 enzymes of the Cyp26 class, which metabolize RA into polar derivatives,function redundantly to shape RA-dependent gene-expression domains during hindbrain development. In zebrafish embryos depleted of the orthologs of the three mammalian CYP26 genes CYP26A1, CYP26B1 and CYP26C1, the entire hindbrain expresses RA-responsive genes that are normally restricted to nested domains in the posterior hindbrain. Furthermore,we show that Cyp26 enzymes are essential for exogenous RA to rescue hindbrain patterning in RA-depleted embryos. We present a `gradient-free' model for hindbrain patterning in which differential RA responsiveness along the hindbrain anterior-posterior axis is shaped primarily by the dynamic expression of RA-degrading enzymes.

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A conserved retinoic acid response element required for early expression of the homeobox gene Hoxb-1

Cited by 431 publications

References 30 publications

In vivo characterization of a vertebrate ultraconserved enhancer

In vivo characterization of a vertebrate ultraconserved enhancer

Induction of HoxB Transcription by Retinoic Acid Requires Actin Polymerization

Cyp26 enzymes generate the retinoic acid response pattern necessary for hindbrain development

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