ReviewSnail/Slug family of repressors: slowly going into the fast lane of development and cancer
Introduction
Genetic and molecular analyses of development and differentiation in the last few decades have yielded large amount of information. A lesson learned is that specific genes are not only required for specific processes, but also used repeatedly at different stages and in various tissues. The driving force of the evolution of these multipurpose genes is not clear, but one possible explanation is the economical advantage of shuffling a limited number of genes to solve the more complex problems facing higher eukaryotes. Another lesson learned is that proteins with conserved motifs control not only common but also distinct processes. But how protein families were generated and how they maintain the common function as well as evolving different functions are all important questions that are yet to yield satisfactory answers.
The development of a singled-celled fertilized egg into a highly organized multicellular adult is a complex process involving series of coordinated events to ensure proper positioning and proper differentiation of progenitor cells. Many transcriptional regulators and signaling molecules have been identified to play key roles in various developmental processes. As increasing genome information becomes available, it is more of the rule than exception that important regulatory molecules identified in one species always have homologs in other species. A good example is the mesoderm determinant snail, which was identified in a large-scale screen for genes that were essential for Drosophila embryonic development. Embryos that are homozygous for loss-of-function of snail exhibit defects in the invagination of the presumptive mesoderm and retraction of the germ band (Grau et al., 1984, Nusslein-Volhard et al., 1984). The morphogenetic defects lead to the formation of a highly twisted embryo, which normally develops into a larva with well-defined cuticle pattern (Fig. 1). Subsequent molecular analysis revealed that the protein contains five zinc fingers and functions as a DNA-binding transcriptional regulator (Boulay et al., 1987, Ip et al., 1992a, Mauhin et al., 1993). The elucidation of the significant role of snail in Drosophila embryogenesis prompted the search for similar genes in other organisms. Since then, homologs of snail have been identified in diverse groups of animals including nematode, protochordates, avian, amphibian, fish, and mammals (Cohen et al., 1998, Corbo et al., 1997, Hammerschmidt and Nusslein-Volhard, 1993, Issac et al., 1997, Jiang et al., 1998, Langeland et al., 1998, Mayor et al., 1995, Metzstein and Horvitz, 1999, Nieto et al., 1992, Nieto et al., 1994, Paznekas et al., 1999, Sargent and Bennett, 1990, Savagner et al., 1997, Smith et al., 1992, Thisse et al., 1995, Thisse et al., 1993, Twigg and Wilkie, 1999, Wada and Saiga, 1999).
In Drosophila, the snail genes family includes three other encoding closely related zinc- finger proteins, escargot, worniu, and scratch (Ashraf et al., 1999, Roark et al., 1995, Whiteley et al., 1992). In the developing central nervous system (CNS) and wing imaginal disc there is functional redundancy among some of these proteins (Ashraf et al., 1999, Fuse et al., 1996, Roark et al., 1995). In vertebrates, each species studied usually possesses at least one Snail gene and a related gene called Slug. The Xenopus Snail and Slug have also been shown to some extent to have redundant functions in neural crest cell migration (Carl et al., 1999). The existence of overlapping functions has added another dimension to the complexity of this important group of transcription factors. Even though many questions remain unanswered, accumulating evidence has implicated the involvement of Snail and related proteins in various aspects of development and differentiation, such as cell fate determination, cell migration, apoptosis, and cancer. With constant emergence of information regarding the functions attributed to both old and new members, it is obvious that the Snail family of proteins is slowly getting into the fast lane of modern biomedical research.
Section snippets
Structural characteristics of the Snail family of proteins
The most conserved feature of the Snail family of proteins is the zinc-finger domain located at the C-terminus. Zinc fingers are one of the most abundant structural motifs based on available genome sequence information (Rubin, 2000). The different classes of zinc fingers include CCHH, CCHC, CCCH, and CCCC, where C and H are the cysteine and histidine residues that constitute the zinc-binding structure. While many of the zinc fingers are employed in nucleic acid binding, an increasing number of
Expression patterns and genetic analyses indicate multiple roles for Snail proteins during development
Utilizing the powerful in situ hybridization technique, different laboratories have revealed the temporal and spatial expression patterns of the snail genes during development in distinct metazoan species. Taken together, the data indicate that the expression appears to correlate with function in the individual organism. Moreover, by comparing the patterns one can conclude that among different species there are common tissues where Snail-related proteins are expressed. They are mesodermal
Snail family of proteins as transcriptional repressors
The zinc-finger domains of Snail and Slug proteins function as sequence-specific DNA-binding motifs. Since the zinc fingers are highly conserved, perhaps it is not too surprising that they recognize similar target sequences. In vitro random selections reveal a recognition consensus 5′-CAGGTG/5′-CACCTG (Fuse et al., 1994, Inukai et al., 1999, Mauhin et al., 1993). It is critical to keep in mind that variants of this core may also bind the proteins well. Transfection experiments in culture cells
Snail family of repressors regulate apoptosis and cancer
Since a major conserved function of Snail proteins is to control cell motility, it is possible that Snail can regulate cancer progression. Cancer is a consequence of series of events including dedifferentiation, uncontrolled cell division, change of cell adhesion properties, and change in invasiveness. A major contribution to cancer progression is the downregulation of cell adhesion molecules, which allows change in cell shape and becomes metastatic (Takeichi, 1993). E-cadherin expression
Evolution of structures and functions
The evolution of structure and function is an interesting question that may never have a straight answer. Nonetheless, we attempt to point out some features which may shed light on the evolution of the different members of the Snail family. First, the target sequence recognition is the most conserved feature and the most important function preserved in all the members. Similar to other families of DNA-binding proteins, probably the rigid target DNA structure requires a very specific protein
Acknowledgements
We thank the anonymous reviewer for many helpful comments. The work related to Snail in our laboratory was supported by the March of Dimes Birth Defects Foundation and the Our Danny Cancer Fund of the Cancer Center at the University of Massachusetts Medical School.
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2019, Developmental BiologyCitation Excerpt :An example of this is highlighted by vertebrate Snail genes (Snail1, Snail2, also known as Snai1 and Snai2), which belong to the Snail superfamily, a group of zinc finger transcription factors with deep phylogenetic origins (Barrallo-Gimeno and Nieto, 2005, 2009; Grau et al., 1984; Manzanares et al., 2001; Nieto, 2002; Nieto et al., 1994; Nüsslein-Volhard et al., 1984). Snail genes likely duplicated from a single ancestral gene present in the last common ancestor of eumetazoans and have since acquired a diverse repertoire of important functions throughout eumetazoan embryogenesis (Barrallo-Gimeno and Nieto, 2009; Hemavathy et al., 2000; Nieto, 2002; Wu and Zhou, 2010). Among eumetazoans, Snail1 and Snail2 are pivotal for mesodermal genesis and patterning (Barrallo-Gimeno and Nieto, 2009; Nieto, 2002).
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