Oscar H. Ocaña

Metastatic Colonization Requires the Repression of the Epithelial-Mesenchymal Transition Inducer Prrx1

The epithelial-mesenchymal transition (EMT) is required in the embryo for the formation of tissues for which cells originate far from their final destination. Carcinoma cells hijack this program for tumor dissemination. The relevance of the EMT in cancer is still debated because it is unclear how these migratory cells colonize distant tissues to form macrometastases. We show that the homeobox factor Prrx1 is an EMT inducer conferring migratory and invasive properties. The loss of Prrx1 is required for cancer cells to metastasize in vivo, which revert to the epithelial phenotype concomitant with the acquisition of stem cell properties. Thus, unlike the classical EMT transcription factors, Prrx1 uncouples EMT and stemness, and is a biomarker associated with patient survival and lack of metastasis.

Reciprocal Repression between Sox3 and Snail Transcription Factors Defines Embryonic Territories at Gastrulation

Summary In developing amniote embryos, the first epithelial-to-mesenchymal transition (EMT) occurs at gastrulation, when a subset of epiblast cells moves to the primitive streak and undergoes EMT to internalize and generate the mesoderm and the endoderm. We show that in the chick embryo this decision to internalize is mediated by reciprocal transcriptional repression of Snail2 and Sox3 factors. We also show that the relationship between Sox3 and Snail is conserved in the mouse embryo and in human cancer cells. In the embryo, Snail-expressing cells ingress at the primitive streak, whereas Sox3-positive cells, which are unable to ingress, ensure the formation of ectodermal derivatives. Thus, the subdivision of the early embryo into the two main territories, ectodermal and mesendodermal, is regulated by changes in cell behavior mediated by the antagonistic relationship between Sox3 and Snail transcription factors.

Snail genes at the crossroads of symmetric and asymmetric processes in the developing mesoderm.

Retinoic acid (RA) signalling ensures that vertebrate mesoderm segmentation is bilaterally synchronized, and corrects transient interferences from asymmetric left–right (L–R) signals involved in organ lateralization. Snail genes participate in both these processes and, although they are expressed symmetrically in the presomitic mesoderm (PSM), Snail1 transcripts are asymmetrically distributed in the L–R lateral mesoderm. We show that the alteration of the symmetric Snail expression in the PSM induces asynchronous somite formation. Furthermore, in the absence of RA signalling, normal asymmetric Snail1 expression in the lateral mesoderm is extended to the PSM, desynchronizing somitogenesis. Thus, Snail1 is the first cue corrected by RA in the PSM to ensure synchronized bilateral segmentation.

A right-handed signalling pathway drives heart looping in vertebrates

Most animals show external bilateral symmetry, which hinders the observation of multiple internal left–right (L/R) asymmetries that are fundamental to organ packaging and function. In vertebrates, left identity is mediated by the left-specific Nodal–Pitx2 axis that is repressed on the right-hand side by the epithelial–mesenchymal transition (EMT) inducer Snail1 (refs 3, 4). Despite some existing evidence, it remains unclear whether an equivalent instructive pathway provides right-hand-specific information to the embryo. Here we show that, in zebrafish, BMP mediates the L/R asymmetric activation of another EMT inducer, Prrx1a, in the lateral plate mesoderm with higher levels on the right. Prrx1a drives L/R differential cell movements towards the midline, leading to a leftward displacement of the cardiac posterior pole through an actomyosin-dependent mechanism. Downregulation of Prrx1a prevents heart looping and leads to mesocardia. Two parallel and mutually repressed pathways, respectively driven by Nodal and BMP on the left and right lateral plate mesoderm, converge on the asymmetric activation of the transcription factors Pitx2 and Prrx1, which integrate left and right information to govern heart morphogenesis. This mechanism is conserved in the chicken embryo, and in the mouse SNAIL1 acts in a similar manner to Prrx1a in zebrafish and PRRX1 in the chick. Thus, a differential L/R EMT produces asymmetric cell movements and forces, more prominent from the right, that drive heart laterality in vertebrates.

A new regulatory loop in cancer-cell invasion

The epithelial‐to‐mesenchymal transition (EMT) converts epithelial cells into mesenchymal cells that are able to invade and migrate. In the context of cancer pathogenesis, the EMT contributes to metastatic progression (Thiery, 2002; Acloque et al , 2008). One of the characteristics of EMT is the functional loss of E‐cadherin, which is crucial for the progression to invasive carcinoma (Perl et al , 1998). Transcriptional repression has emerged as a fundamental mechanism for E‐cadherin loss during EMT and several repressors have been characterized. These include zinc‐finger E‐box‐binding homeo box 1 (ZEB1), ZEB2/SIP1, Snail1, Snail2 and Twist, which strongly repress E‐cadherin transcription through their direct binding to the E‐box motifs within the E‐cadherin promoter (Barrallo‐Gimeno & Nieto, 2005; Peinado et al , 2007). During the past decade, it has emerged that microRNAs (miRNAs) are a fundamental mechanism of gene‐expression regulation, and several recent reports have shown that these small molecules are involved in the control of E‐cadherin expression in cancer cells and tumours (Hurteau et al , 2007; Christoffersen et al , 2007; Gregory et al , 2008; Park et al , 2008). Furthermore, in this issue of EMBO reports , Burk and colleagues have provided a beautiful example of gene regulation in which miRNAs and transcription factors are linked to one another in a gene‐regulatory network to control E‐cadherin expression and the invasive phenotype in cancer cells (Burk et al , 2008). MiRNAs regulate gene expression through binding to mRNA target sequences typically in their 3′ untranslated regulatory regions …

Actiniaria and Ceriantharia of the Azores (Cnidaria Anthozoa)

The common shallow water species of sea anemones (Actiniaria) and tube anemones (Ceriantharia) of the Azores are listed. Eight species of sea anemones are mentioned, the species Cereus pedunculatus and Sagartia affinis being new records for the archipelago. Both species of Ceriantharia, namely Arachnanthus nocturnus and Pachycerianthus solitarius, are recorded from the Azores for the first time. Arachnanthus nocturnus is also recorded from the Cape Verde Islands and from Madeira for the first time.

Snail2 and Zeb2 repress P-Cadherin to define embryonic territories in the chick embryo

Snail and Zeb transcription factors induce epithelial-to-mesenchymal transition (EMT) in embryonic and adult tissues by direct repression of E-cadherin transcription. The repression of E-cadherin transcription by the EMT inducers Snail1 and Zeb2 plays a fundamental role in defining embryonic territories in the mouse, as E-cadherin needs to be downregulated in the primitive streak and in the epiblast, concomitant with the formation of mesendodermal precursors and the neural plate, respectively. Here, we show that in the chick embryo, E-cadherin is weakly expressed in the epiblast at pre-primitive streak stages where it is substituted for by P-cadherin. We also show that Snail2 and Zeb2 repress P-cadherin transcription in the primitive streak and the neural plate, respectively. This indicates that E- and P-cadherin expression patterns evolved differently between chick and mouse. As such, the Snail1/E-cadherin axis described in the early mouse embryo corresponds to Snail2/P-cadherin in the chick, but both Snail factors and Zeb2 fulfil a similar role in chick and mouse in directly repressing ectodermal cadherin genes to contribute to the delamination of mesendodermal precursors at gastrulation and the proper specification of the neural ectoderm during neural induction. Summary: Sequential P-cadherin repression in the primitive streak and the neural plate defines embryonic territories during early chick embryonic development.

Mutual exclusion of transcription factors and cell behaviour in the definition of vertebrate embryonic territories

Early embryonic territories are transient entities under permanent remodelling to form newly derived cell populations that will eventually give rise to the adult tissues and organs. A vast effort has been devoted to identifying the determinants and mechanisms that define embryonic territories. Indeed, studies in the vertebrate embryo from the morula stage to the segregation of the main embryonic layers-ectoderm, mesoderm and endoderm-have highlighted the importance of the mutual exclusion/repression between pairs of transcription factors, in coordination with the control exerted over cell division, adhesion and motility.