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First published online June 27, 2005
doi: 10.1242/10.1242/dev.01907

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The Snail genes as inducers of cell movement and survival: implications in development and cancer

Instituto de Neurociencias de Alicante CSIC-UMH, Apartado 18, Sant Joan d'Alacant, 03550, Spain

View larger version (49K): [in a new window]   Fig. 1. Phylogenetic tree of the Snail superfamily. This tree is updated from a previous version (Nieto, 2002) with 22 new members. The different family members are grouped into two families: Snail (blue) and Scratch (pink). Vertebrates have three Snail members: Snail1 (previously Snail), Snail2 (previously Slug) and Snail3 (previously Smuc). Am, Acropora millepora (coral); Bf, Branchiostoma floridae (amphioxus); Ce, Caenorhabditis elegans (nematode); Ci, Ciona intestinalis (ascidia); Cs, Cupiennius salei (spider); Dm, Drosophila melanogaster (fruitfly); Dr, Danio rerio (zebrafish); Em, Eublepharis macularius (gecko); Gg, Gallus gallus (chicken); Hr, Halocynthia roretzi (ascidian); Hro, Helobdella robusta (leech); Hs, Homo sapiens (human); Lv, Lytechinus variegatus (green sea urchin); Mc, Mauremys caspica (turtle); Mm, Mus musculus (mouse); Nv, Nematostella vectensis (anemone); Pc, Podocoryne carnea (jellyfish); Pv, Patella vulgata (mollusc); Sc, Scyliorhinus canicula (shark); Sp, Strongylocentrotus purpuratus (sea urchin); Tr, Takifugu rubripes (pufferfish); Xl, Xenopus laevis (African clawed toad); Xt, Xenopus tropicalis (western clawed frog).

View larger version (52K): [in a new window]   Fig. 2. Evolutionary history of the Snail gene superfamily. Duplication of a Snail gene in the metazoan ancestor probably gave rise to two highly related genes, Snail and Scratch. Independent duplications in Cnidarians, Protostomes and Deuterostomes gave rise to several family members in each group. Ancestral genes are shown in red and predicted members in grey, while existing genes are in black. Updated from Nieto (Nieto, 2002).

View larger version (32K): [in a new window]   Fig. 3. Snail genes are a convergence point in EMT induction. Numerous signalling pathways induce the epithelial to mesenchymal transition (EMT), and all have been shown to activate the expression of Snail genes. Below each extracellular signal are the tissues and processes in which they have been studied. In addition to being tightly regulated at the transcriptional level, Snail activity is also regulated by its subcellular localisation, which is governed by at least two kinases GSK3 and PAK1, and by the zinc-finger transporter LIV1. (See text for details.) AMF, autocrine motility factor; E-cad, E-cadherin; EGF, epidermal growth factor; FGF, fibroblast growth factor; BMP, bone morphogenetic protein; ILK, integrin-linked kinase; MTA3, metastasis-associated protein 3; PAK1; p21-activated kinase; TGFß, transforming growth factor ß; PTH(rP)R, parathyroid hormone related peptide receptor; SCF, stem cell factor.

View larger version (18K): [in a new window]   Fig. 4. Downstream targets of Snail. Snail gene expression induces the loss of epithelial markers and the gain of mesenchymal markers, as well as inducing changes in cell shape, and changes related to morphology and to the acquisition of motility and invasive properties. The Snail genes also regulate cell proliferation and cell death. Not all of these targets are directly regulated by Snail genes: because Snail genes function as repressors, from Drosophila to humans (reviewed by Nieto, 2002), target upregulation might be due to the Snail-mediated repression of a repressor. However, their role as activators cannot be excluded. The molecules and processes shown in red are downregulated or impaired by Snail, and those in green are upregulated or promoted by Snail. BID, Bcl-interacting death agonist; CDK, cyclin-dependent kinase; DFF, DNA fragmentation factor; ERKs, extracellular signal-regulated kinases; MMPs, metalloproteinases; PI3K, phosphoinositide 3-kinase; p21, cyclin-dependent kinase inhibitor; p53, tumour suppressor; Rb, retinoblastoma; XR11, Xenopus Bcl-xL homologue.

View larger version (35K): [in a new window]   Fig. 5. Snail functions in development and disease. The cellular properties conferred by Snail expression are beneficial under normal circumstances, but can be fatal in pathological situations.