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  • Review Article
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The snail superfamily of zinc-finger transcription factors

Nature Reviews Molecular Cell Biology volume 3, pages 155–166 (2002)Cite this article

Key Points

  • Snail family members are thought to act as transcriptional repressors. The zinc fingers correspond to the C2H2 type (cysteine/histidine) and bind to a site that contains six bases, CAGGTG. This motif is identical to the E box, the core-binding site of basic helix–loop–helix transcription factors.

  • Snail homologues have been found in many species including humans, other vertebrates, non-vertebrate chordates (ascidians and Amphioxus), insects, nematodes, annelids and molluscs.

  • They constitute a superfamily that can be subdivided into two related but independent groups: the Snail and the Scratch families. Independent duplication events of one Snail and one Scratch gene that were present in the metazoan ancestor, gave rise to three genes of each group in Drosophila and two for each group in most vertebrates.

  • They show a conserved function in mesoderm development from flies to mammals, and vertebrate family members participate in the specification and migration of the neural crest. The role in delamination and migration is mediated by the triggering of the epithelial–mesenchymal transition (EMT), a phenotypic change that renders epithelial cells migratory and invasive.

  • Snail induces EMT by directly repressing the transcription of E-cadherin.

  • EMT processes also occur during the malignant conversion of epithelial tumours, and pathological activation of Snail has been shown at the invasive front of chemically induced mouse skin tumours and in human breast carcinomas.

  • The expression of the two vertebrate family members, Snail and Slug, diverges at the sites of EMT in different species. Whereas in the chick, Slug is expressed in the premigratory neural crest and the primitive streak, and Snail is absent from these tissues, in the mouse embryo, Snail is expressed in these cells. Expression in zebrafish and Xenopus is more similar to that in the mouse. Interesting questions emerge, such as functional equivalence and the evolutionary mechanisms that led to those differences.

  • Different signalling pathways —TGF-β, BMP, FGF and Wnt — have been implicated in the induction of Snail family members during the process of EMT.

  • Different superfamily members (scratch in C. elegans and Slug in mammals) are involved in the regulation of cell death and survival.

  • Escargot and mouse Snail are involved in the control of polyploidy in several tissues, including imaginal discs cells in Drosophila, mouse trophoblast cells and human megakaryocytes.

  • A deficiency in the three Drosophila Snail family members leads to an inappropriate subcellular localization of determinants that are crucial for cell-fate decisions during asymmetric cell division.

  • An ancestral function in the development of sensory and/or neuronal structures is proposed for the whole superfamily, which includes both the Snail and Scratch genes. An additional ancestral function in the control of cell death/survival is also proposed.

  • The role of EMT seems to be exclusively associated with the members of the Snail family with representatives analysed in lophotrochozoans, ecdysozoans and deuterostomes. This role has been co-opted for cell migration during mesoderm and neural-crest formation, and tumour progression, when these processes emerged.

Abstract

The Snail superfamily of zinc-finger transcription factors is involved in processes that imply pronounced cell movements, both during embryonic development and in the acquisition of invasive and migratory properties during tumour progression. Different family members have also been implicated in the signalling cascade that confers left–right identity, as well as in the formation of appendages, neural differentiation, cell division and cell survival.

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Figure 1: Phylogenetic tree of the Snail superfamily.
Figure 2: Sequence comparison of the main conserved domains and consensus sequences for the individual zinc fingers of the Snail superfamily.
Figure 3: Expression of Snail family members in Drosophila, amphioxus, chick and mouse embryos.
Figure 4: Snail genes occupy a central position in triggering EMT in physiological and pathological situations.
Figure 5: Different genetic pathways involving Snail function.

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Acknowledgements

I am very grateful to people in the lab for their work along the years and for their encouraging discussions. Work in the lab is, at present, supported by grants from the Spanish Ministries of Science and Technology (DGESIC) and Health (FIS), and from the Local Government (Comunidad Autónoma de Madrid).

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  1. Instituto Cajal, Doctor Arce, 37, Madrid, 28002, Spain

    M. Angela Nieto

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DATABASES

FlyBase

CtBP

deadpan

RhoGEF2

Escargot

Fog

rhomboid

scratch

single-minded

String

snail

Tribbles

worniu

 LocusLink

BCL-XL

ILK

 Swiss-Prot

β-catenin

cytokeratin-18

desmoplakin

E-cadherin

FGFR1

fibronectin

Gfi1

HLF

Lef-1

Muc-1

Nodal

PTH(rP)

RhoB

SIP1

Slug

Smuc

snail1

snail2

TGF-β1

TGF-β2

vimentin

 WormBase

ces-1

CES-2

CED-3

CED-4

ced-9

EGL-1

Glossary

GASTRULATION

The morphogenetic movements of the early embryo that lead to the generation of the third embryonic layer — the mesoderm.

MESODERM

The third embryonic layer generated during gastrulation, which occupies an intermediate position between the ectoderm and the endoderm. It will give rise to the skeleton, muscles and connective tissue.

TRIPOBLAST

An animal that is composed of three embryonic cell layers: ectoderm, endoderm and mesoderm.

NEURAL CREST

A cell population that originates in the dorsal part of the neural tube and gives rise to many derivatives, including most of the peripheral nervous system, the cranio-facial skeleton and pigmented cells of the body.

EPITHELIAL–MESENCHYMAL TRANSITION

The transformation of an epithelial cell into a mesenchymal cell with migratory and invasive properties.

BODY PLAN

The organization of the embryonic tissues to generate an individual with specific characters.

CHORDATE

An animal with a notochord. These include ascidians, amphioxus and all vertebrates.

NEMATODE

An unsegmented worm.

ANNELID

A segmented worm.

BASIC HELIX–LOOP–HELIX PROTEIN

A transcription factor with a basic domain that binds to a hexanucleotide called the E box, and a hydrophobic domain (the helix–loop–helix) that allows the formation of homo- and heterodimers. They can also have leucine repeats called a leucine zipper.

LOPHOTROCHOZOAN

This group includes two important animal groups, the Lophophorata (brachiopods, flat worms and nemerteans) and the Trochozoa (molluscs and annelids).

EPIDERMAL PLACODE

An epidermal thickening in the embryonic head that differentiates into neurons, as well as into other cell types, at the sites at which the sense organs will form.

PRIMITIVE STREAK

A structure that is formed at the posterior end of amniote embryos at gastrulation stages. An area of mesoderm formation.

METAZOA

The animal kingdom. Includes sponges, diploblasts, protostomes and deuterostomes.

PROTOSTOME

An animal in which the mouth develops from the first opening that develops in the embryo. These include ecdysozoans and lophotrochozoans.

DEUTEROSTOME

An animal in which the anus develops from the first opening of the embryo, and the mouth is formed later. These include echinoderms and chordates.

E-CADHERIN

The main cell–cell adhesion molecule, which is central in maintaining the integrity of epithelial tissues, both in physiology and pathology.

ADHERENS JUNCTION

A cell–cell and cell–extracellular matrix adhesion complex that is composed of integrins and cadherins that are attached to cytoplasmic actin filaments.

PARIETAL ENDODERM

The extraembryonic tissue that is derived from the primitive endoderm and visceral endoderm, and is composed of motile cells that secrete high amounts of extracellular matrix.

PRIMITIVE ENDODERM

The extraembryonic tissue that gives rise to the visceral and parietal endoderm.

VISCERAL ENDODERM

The extraembryonic cell layer that is involved in nutrient uptake and transport.

INVASIVENESS

The ability to degrade and migrate through the extracellular matrix.

CDC25

A family of protein phosphatases that dephosphorylate cyclin-dependent kinases during cell-cycle progression.

IMAGINAL DISCS

The primordia of different adult structures that are present in the larvae of insects with complete metamorphosis.

TROPHOBLAST

The extraembryonic epithelial tissue that is crucial for formation of the placenta.

ENDOREDUPLICATION

The process by which the cells pass to rounds of DNA duplication in the absence of a mitotic division.

ASYMMETRIC CELL DIVISION

A process by which a cell gives rise to two different descendants after division.

GANGLION MOTHER CELL

One of the daughters of a Drosophila neuroblast after asymmetric cell division. It divides once more to give rise to two post-mitotic neurons.

LEFT–RIGHT ASYMMETRY

The differences along the left–right axis of the body.

HEART SITUS

The position of the heart with respect to the left–right axis of the body.

ECDYSOZOANS

One of the important groups within the animal kingdom, it includes arthropods and nematodes.

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Nieto, M. The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol 3, 155–166 (2002). https://doi.org/10.1038/nrm757

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