Snail1a and Snail1b cooperate in the anterior migration of the axial mesendoderm in the zebrafish embryo

Blanco, Marı́a José; Barrallo-Gimeno, Alejandro; Acloque, Hervé; Reyes, Ariel E.; Tada, Masazumi; Allende, Miguel L.; Mayor, Roberto; Nieto, Manuel

doi:10.1242/dev.006858

Cited by 74 publications

(82 citation statements)

References 39 publications

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“…4B, the existence of seven possible phases (the corresponding nullclines are included in SI Appendix, Section 10): (i) monostable phenotypes-{E}, {M}, and {E/M}; (ii) coexistence of two phenotypes-{E, M}, {E, E/M}, and {E/M, M}; and (iii) coexistence of all three phenotypes-{E, E/M, M}. The richness of these identified phases can help explain experiments regarding the diverse behaviors triggered by SNAIL (34)(35)(36) in inducing EMT. According to the rate of SNAIL increase and to the details of how it is increased (e.g., by TFG-β or hypoxia, which also affect the level of ZEB), the cells will follow a different trajectory in the phase diagram and thus will go through different phenotypic transitions.…”

Section: Resultsmentioning

confidence: 99%

MicroRNA-based regulation of epithelial–hybrid–mesenchymal fate determination

Jolly

Levine

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

487

707

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Forward and backward transitions between epithelial and mesenchymal phenotypes play crucial roles in embryonic development and tissue repair. Aberrantly regulated transitions are also a hallmark of cancer metastasis. The genetic network that regulates these transitions appears to allow for the existence of a hybrid phenotype (epithelial/mesenchymal). Hybrid cells are endowed with mixed epithelial and mesenchymal characteristics, enabling specialized capabilities such as collective cell migration. Cell-fate determination between the three phenotypes is in fact regulated by a circuit composed of two highly interconnected chimeric modules-the miR-34/SNAIL and the miR-200/ZEB mutual-inhibition feedback circuits. Here, we used detailed modeling of microRNAbased regulation to study this core unit. More specifically, we investigated the functions of the two isolated modules and subsequently of the combined unit when the two modules are integrated into the full regulatory circuit. We found that miR-200/ZEB forms a tristable circuit that acts as a ternary switch, driven by miR-34/ SNAIL, that is a monostable module that acts as a noise-buffering integrator of internal and external signals. We propose to associate the three stable states-(1,0), (high miR-200)/(low ZEB); (0,1), (low miR-200)/(high ZEB); and (1/2,1/2), (medium miR-200)/(medium ZEB)-with the epithelial, mesenchymal, and hybrid phenotypes, respectively. Our (1/2,1/2) state hypothesis is consistent with recent experimental studies (e.g., ZEB expression measurements in collectively migrating cells) and explains the lack of observed mesenchymalto-hybrid transitions in metastatic cells and in induced pluripotent stem cells. Testable predictions of dynamic gene expression during complete and partial transitions are presented. multistable decision circuit | partial EMT | cancer systems biology | microRNA modeling | metastable intermediate phenotypes U nderstanding cell-fate decisions during embryonic development and tumorigenesis remains a major research challenge in modern developmental and cancer biology (1). Over recent years, we have witnessed rapid progress in mapping the gene regulatory networks associated with cellular phenotype with applications to transitions from epithelial to mesenchymal modalities, to the differentiation of pluripotent stem cells into progenitor cells, to the existence and role of cancer stem-like cells (CSC), and to the production of induced pluripotent stem cells (iPSCs). Cellfate determinations in all of these examples involve changes in expression of various transcription factors (TFs) and microRNAs (miRNAs) that regulate cascades of regulatory networks, ultimately generating genome-wide gene-expression patterns and concomitant protein levels corresponding to a particular cell lineage (fate).The E/M Hybrid Phenotype. An archetypal example of cell-fate decisions concerns the forward and backward transitions between the epithelial (E) and mesenchymal (M) phenotypes (EMT and MET), transitions that play a critical role in embryonic deve...

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Section: Resultsmentioning

confidence: 99%

MicroRNA-based regulation of epithelial–hybrid–mesenchymal fate determination

Jolly

Levine

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

487

707

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“…Human cytokine array showed several cytokines differentially released by tumor cells expressing SNAI1; most of these released cytokines have a major function in monocyte-macrophage recruitment and pro-inflammatory activities, opening an interesting link between SNAI1 and inflammation, which deserves further investigation. Likewise, it was recently described that SNAI1 proteins influence the behavior of Snai1-negative neighboring cells in zebrafish embryo (Blanco et al, 2007). Although we performed a proteomic analysis looking for differences between conditioned media from SW480-ADH-Mock and SW480-ADH-Snai1, we did not identify proteins with an acknowledged paracrine function.…”

Section: Adh-gfp Adh-sn Row Column Cytokine Cytokinefull Name Median mentioning

confidence: 88%

SNAI1 expression in colon cancer related with CDH1 and VDR downregulation in normal adjacent tissue

et al. 2009

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SNAI1, ZEB1, E-cadherin (CDH1), and vitamin D receptor (VDR) genes regulate the epithelial-mesenchymal transition (EMT) that initiates the invasion process of many tumor cells. We hypothesized that this process could also affect the behavior of normal cells adjacent to the tumor. To verify this hypothesis, the expression level of these genes was determined by quantitative RT-PCR in tumor, normal adjacent, and normal distant tissues from 32 colorectal cancer (CC) patients. In addition, we extended the study to human HaCaT normal keratinocytes and SW480-ADH colon cancer cells co-cultured with SW480-ADH cells overexpressing the mouse Snai1 gene. Of 18 CC cases with SNAI1 expression in tumor tissue, five also had SNAI1 in normal adjacent tissue (NAT). Expression of SNAI1 in tumor tissue correlated with downregulation of CDH1 and VDR genes in both tumor (P ¼ 0.047 and P ¼ 0.014, respectively) and NAT lacking SNAI1 expression (P ¼ 0.054 and P ¼ 0.003). ZEB1 expression was directly related to VDR expression in tumor tissue (r ¼ 0.39; P ¼ 0.027) and inversely to CDH1 in NAT (r ¼ À0.46; P ¼ 0.010). CDH1 and VDR were also downregulated in SW480-ADH and MaCaT cells, respectively, when they were co-cultured with Snai1-expressing cells. Furthermore, cytokine analysis showed differences in the conditioned media obtained from the two cell types. These results indicate that histologically normal tissue adjacent to tumor tissue expressing the EMT-inducing gene SNAI1 shows alterations in the expression of epithelial differentiation genes such as CDH1 and VDR.

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“…Since its discovery, Snai1/2 has been linked to EMT in many systems, from cancer cell lines to gastrulating embryos (Nieto et al, 1994;Blanco et al, 2007). In the neural crest, Snai1/2 functions as a transcriptional repressor and plays an important role in the downregulation of the type 1 cadherins during EMT.…”

Section: Transcriptional Control Of the Neural Crest Emt Programmentioning

confidence: 99%

Establishing neural crest identity: a gene regulatory recipe

2015

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The neural crest is a stem/progenitor cell population that contributes to a wide variety of derivatives, including sensory and autonomic ganglia, cartilage and bone of the face and pigment cells of the skin. Unique to vertebrate embryos, it has served as an excellent model system for the study of cell behavior and identity owing to its multipotency, motility and ability to form a broad array of cell types. Neural crest development is thought to be controlled by a suite of transcriptional and epigenetic inputs arranged hierarchically in a gene regulatory network. Here, we examine neural crest development from a gene regulatory perspective and discuss how the underlying genetic circuitry results in the features that define this unique cell population.

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Snail1a and Snail1b cooperate in the anterior migration of the axial mesendoderm in the zebrafish embryo

Cited by 74 publications

References 39 publications

MicroRNA-based regulation of epithelial–hybrid–mesenchymal fate determination

MicroRNA-based regulation of epithelial–hybrid–mesenchymal fate determination

SNAI1 expression in colon cancer related with CDH1 and VDR downregulation in normal adjacent tissue

Establishing neural crest identity: a gene regulatory recipe

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