Human transcription factor SLUG: mutation analysis in patients with neural tube defects and identification of a missense mutation (D119E) in the Slug subfamily-defining region

Stegmann, Karolin; Boecker, Julia; Kosan, Christian; Ermert, August; Kunz, Jürgen; Koch, Manuela C.

doi:10.1016/s1383-5726(99)00002-3

Cited by 15 publications

(12 citation statements)

References 18 publications

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“…Snail2 and p53 play key roles during neural tube closure in many organisms, including humans (Pangilinan et al, 2008;Stegmann et al, 1999). Indeed, we observed a large number of neural tube defects (NTDs) in our experiments (data not shown), in agreement with a role for the p53-Snail2 regulatory loop in such defects.…”

Section: P53-snail2 Regulatory Loopsupporting

confidence: 82%

p53 coordinates cranial neural crest cell growth and epithelial-mesenchymal transition/delamination processes

et al. 2011

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SUMMARYNeural crest development involves epithelial-mesenchymal transition (EMT), during which epithelial cells are converted into individual migratory cells. Notably, the same signaling pathways regulate EMT function during both development and tumor metastasis. p53 plays multiple roles in the prevention of tumor development; however, its precise roles during embryogenesis are less clear. We have investigated the role of p53 in early cranial neural crest (CNC) development in chick and mouse embryos. In the mouse, p53 knockout embryos displayed broad craniofacial defects in skeletal, neuronal and muscle tissues. In the chick, p53 is expressed in CNC progenitors and its expression decreases with their delamination from the neural tube. Stabilization of p53 protein using a pharmacological inhibitor of its negative regulator, MDM2, resulted in reduced SNAIL2 (SLUG) and ETS1 expression, fewer migrating CNC cells and in craniofacial defects. By contrast, electroporation of a dominant-negative p53 construct increased PAX7 + SOX9 + CNC progenitors and EMT/delamination of CNC from the neural tube, although the migration of these cells to the periphery was impaired. Investigating the underlying molecular mechanisms revealed that p53 coordinates CNC cell growth and EMT/delamination processes by affecting cell cycle gene expression and proliferation at discrete developmental stages; disruption of these processes can lead to craniofacial defects.

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Section: P53-snail2 Regulatory Loopsupporting

confidence: 82%

p53 coordinates cranial neural crest cell growth and epithelial-mesenchymal transition/delamination processes

et al. 2011

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“…These conserved sequences are not present in the 5Ј-flanking regions of the human (19) and mouse 3 Slug genes, but this is consistent with the observed differences in the Slug expression pattern between Xenopus and mouse (33). The only sequence conserved between these four species is a 20-bp motif at the 5Ј-end of region B in Xenopus, suggesting that this motif may be involved in regulation.…”

Section: The Xslug Promoter Is An Efficient Tool For Targetingsupporting

confidence: 82%

“…The predicted amino acid sequence of the protein encoded by the X. tropicalis gene is very similar to that of the published X. laevis Slug sequence (7), with 99% identity overall and all five zinc fingers totally identical. The organization of the gene is identical to that of the human gene (19), consisting of two short introns (of 700 bp and 1 kb, respectively) located at the same relative positions in the coding region in both species.…”

Section: Resultsmentioning

confidence: 93%

“…Comparison of the sequences of Slug promoters from X. tropicalis, humans (19), and mice 3 revealed no similarity except a common 20-bp region, located at Ϫ3.2 kb in X. tropicalis, Ϫ1.5 kb in humans, and Ϫ1.2 kb in mice. We designed two primers in this common region and used them with two primers corresponding to the Slug coding region to perform nested PCR on X. laevis genomic DNA.…”

Section: Resultsmentioning

confidence: 99%

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Cloning and Characterization of ThreeXenopus Slug Promoters Reveal Direct Regulation by Lef/β-Catenin Signaling

Vallin

Thuret

Giacomello

et al. 2001

Journal of Biological Chemistry

158

139

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In amphibians and birds, one of the first steps of neural crest cell (NCC) determination is expression of the transcription factor Slug. This marker has been used to demonstrate that BMP and Wnt molecules play a major role in NCC induction. However, it is unknown whether Slug expression is directly or indirectly regulated by these signals. We report here the cloning and characterization of three Xenopus Slug promoters: that of the Xenopus tropicalis slug gene and those of two Xenopus laevis Slug pseudoalleles. Although the three genes encode proteins with almost identical amino acid sequences and are expressed with similar spatiotemporal patterns, their 5-flanking regions are quite different. A striking difference is a deletion in the X. tropicalis gene located precisely at the transcription initiation site that results in the X. tropicalis promoter being inefficient in X. laevis. Additionally, we identified two regions common to the three promoters that are necessary and sufficient to drive specific expression in NCCs. Interestingly, one of the common regulatory regions presents a functional Lef/␤-catenin-binding site necessary for specific expression. As the Lef⅐␤-catenin complex is a downstream effector of Wnt signaling, these results suggest that Xenopus Slug is a direct target of NCC determination signals.

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“…Three conserved cis-elements were identified in the proximal region of the slug gene, by comparing the Xenopus sequences with the human (29), mouse (30), and chicken 2 slug gene sequences (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

YY1 Regulates the Neural Crest-associated slug Gene in Xenopus laevis

Morgan

Woltering

Rieden

et al. 2004

Journal of Biological Chemistry

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slug gene expression is associated with the specification and migration of neural crest cells in the African clawed frog Xenopus laevis. We provide evidence that the protein Ying-Yang 1 (YY1) regulates the slug gene expression both indirectly and directly, via a YY1 ciselement in the slug promoter, during Xenopus development. The ability of the YY1 to bind this YY1 cis-element was confirmed by electromobility shift assays and reporter assays. YY1 was detected in the nuclei of ectodermal cells contemporaneously with the process of neural crest specification. The injection of anti-YY1 morpholino, which targeted both YY1␣ and YY1␤ gene products, depleted YY1 expression below 20% and was lethal at gastrulation. Sublethal depletion of YY1 reduced the length of the anterior-posterior axis and severely inhibited the expression of the neural marker Nrp1 and of the slug gene. Overexpression of YY1 or mutation of the YY1 cis-element reduced the restricted spatial expression of the slug reporter gene in the neural ectoderm border and provoked its expression in the nonneural ectoderm. Chromatin immunoprecipitation indicated that endogenous YY1 interacts directly with the YY1 cis-element of the endogenous slug gene and with the slug gene reporter sequence injected into embryos. The results suggest that YY1 is essential for Xenopus development; is necessary for neural ectoderm differentiation, a prerequisite for neural crest specification; and restricts which cells can form neural crest mesenchyme through directly blocking slug gene activity.

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Human transcription factor SLUG: mutation analysis in patients with neural tube defects and identification of a missense mutation (D119E) in the Slug subfamily-defining region

Cited by 15 publications

References 18 publications

p53 coordinates cranial neural crest cell growth and epithelial-mesenchymal transition/delamination processes

p53 coordinates cranial neural crest cell growth and epithelial-mesenchymal transition/delamination processes

Cloning and Characterization of ThreeXenopus Slug Promoters Reveal Direct Regulation by Lef/β-Catenin Signaling

YY1 Regulates the Neural Crest-associated slug Gene in Xenopus laevis

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