Snail family genes encode DNA binding zinc finger proteins that act as transcriptional repressors. Mouse embryos deficient for the Snail (Sna) gene exhibit defects in the formation of the mesoderm germ layer. In Sna ؊/؊ mutant embryos, a mesoderm layer forms and mesodermal marker genes are induced but the mutant mesoderm is morphologically abnormal. Lacunae form within the mesoderm layer of the mutant embryos, and cells lining these lacunae retain epithelial characteristics. These cells resemble a columnar epithelium and have apical-basal polarity, with microvilli along the apical surface and intercellular electron-dense adhesive junctions that resemble adherens junctions. E-cadherin expression is retained in the mesoderm of the Sna ؊/؊ embryos. These defects are strikingly similar to the gastrulation defects observed in snail-deficient Drosophila embryos, suggesting that the mechanism of repression of E-cadherin transcription by Snail family proteins may have been present in the metazoan ancestor of the arthropod and mammalian lineages.Genes of the Snail family encode zinc finger proteins that function as transcriptional repressors in a variety of experimental systems (8,10,12,16,17,21; reviewed in reference 11). The first gene of this family studied was the Drosophila snail gene, which is one of two genes required zygotically for mesoderm formation during Drosophila embryogenesis (1, 5, 9, 13, 24; reviewed in reference 19). Embryos homozygous for null mutations of snail exhibit defects in mesoderm formation, gastrulation movements, and germ band retraction (9, 24). The snail protein is a transcriptional repressor which acts to maintain proper germ layer boundaries by repressing the expression within the mesoderm of regulatory genes involved in ectodermal development (18). Snail family genes are evolutionarily conserved, and studies have implicated Snail family proteins in the regulation of epithelial-mesenchymal transitions in tissue culture systems and in both vertebrate and invertebrate embryos (3,7,17,19,20,23,26,27).Two mouse homologs of snail, termed Sna and Slug, have been cloned (15,22,28,30). It has been previously demonstrated that mice homozygous for a null mutation of the Slug gene are viable, although they exhibit postnatal growth deficiency (15). We describe here the construction and analysis of a targeted mutation of the Sna gene. During gastrulation, Sna is expressed in the primitive streak and the mesoderm germ layer (22,30). Sna-deficient mouse embryos die early in gestation, exhibiting defects in gastrulation and mesoderm formation. MATERIALS AND METHODSGene targeting. The Sna targeting vector was constructed from an 18-kb genomic clone containing the entire Sna gene (14). The 5Ј arm was a 2.5-kb SalI-NruI genomic fragment subcloned upstream of a PGK-neo expression cassette. The 3Ј arm was a 1.2-kb XbaI-EcoRI fragment. This resulted in the deletion of a 1.6-kb genomic fragment containing exons 1 and 2 of the Sna gene, which deletes the translation initiation site and amino acids 1 to 203 of t...

Palate development requires precise regulation of gene expression changes,morphogenetic movements and alterations in cell physiology. Defects in any of these processes can result in cleft palate, a common human birth defect. The Snail gene family encodes transcriptional repressors that play essential roles in the growth and patterning of vertebrate embryos. Here we report the functions of Snail (Snai1) and Slug (Snai2) genes during palate development in mice. Snai2-/- mice exhibit cleft palate, which is completely penetrant on a Snai1 heterozygous genetic background. Cleft palate in Snai1+/- Snai2-/-embryos is due to a failure of the elevated palatal shelves to fuse. Furthermore, while tissue-specific deletion of the Snai1 gene in neural crest cells does not cause any obvious defects, neural-crest-specific Snai1 deletion on a Snai2-/- genetic background results in multiple craniofacial defects, including a cleft palate phenotype distinct from that observed in Snai1+/-Snai2-/- embryos. In embryos with neural-crest-specific Snai1 deletion on a Snai2-/- background, palatal clefting results from a failure of Meckel's cartilage to extend the mandible and thereby allow the palatal shelves to elevate, defects similar to those seen in the Pierre Robin Sequence in humans.

Saethre-Chotzen syndrome is a common autosomal dominant form of craniosynostosis, the premature fusion of the sutures of the calvarial bones of the skull. Most Saethre-Chotzen syndrome cases are caused by haploinsufficiency for the TWIST gene. Mice heterozygous for a null mutation of the Twist gene replicate certain features of Saethre-Chotzen syndrome, but have not been reported to exhibit craniosynostosis. We demonstrate that Twist heterozygous mice exhibit fusions of the coronal suture and other cranial suture abnormalities, indicating that Twist heterozygous mice constitute a better animal model for Saethre-Chotzen syndrome than was previously appreciated. Anat Rec 268: 90 -92, 2002.

The vertebrate Slug gene encodes a zinc finger-containing transcriptional repressor. Here we report expression of the mouse Slug gene during organogenesis and late fetal development using histochemical detection of ␤-galactosidase expressed from a targeted Slug lacZ knock-in allele. The Slug gene is highly expressed in the mesenchymal or stromal component of numerous organs. It is also highly expressed in craniofacial mesenchyme, in bone of both mesodermal and neural crest origin, and in the outflow tract and the endocardial cushions of the heart. Anat Rec Part A 271A: 189 -191, 2003.

In Drosophila, mutations in the Twist gene interact with mutations in the Snail gene. We show that the mouse Twist1 mutation interacts with Snai1 and Snai2 mutations to enhance aberrant cranial suture fusion, demonstrating that genetic interactions between genes of the Twist and Snail families have been conserved during evolution.