Multiple functions of Snail family genes during palate development in mice

Abstract

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.

Palatogenesis: morphogenetic and molecular mechanisms of secondary palate development

“…4). Members of the Snail family of transcription factors are crucial regulators of palatal fusion, as Snai1 +/-; Snai2 +/-compound mutants display failure of fusion concomitant with a reduction in MES apoptosis (Murray et al, 2007). Tgfb3 expression was not affected in these mutants, however, indicating that these transcription factors regulate palatal fusion downstream of, or in parallel to, the Tgf3 pathway.…”

Epithelial-Mesenchymal Transitions in development and disease: old views and new perspectives

“…Antisense oligonucleotides against Slug (now called Snail2) prevented neural crest and mesoderm delamination (Nieto et al, 1994) and subsequently, it was confirmed that Snail genes are crucial for the induction of EMT in different species and tissues (reviewed in Hemavathy et al, 2000;Nieto, 2002;Ip and Gridley, 2002;De Craene et al, 2005;Barrallo-Gimeno and Nieto, 2005). As such, in addition to the neural crest and the mesoderm, Snail genes participate in the EMT necessary for the formation of the heart cushions (Romano and Runyan, 2000;Carmona et al, 2000;Timmerman et al, 2004), the parietal endoderm (Velmaat et al, 2000) and the closure of the palate (Martinez-Alvarez et al, 2004;Murray et al, 2007), as well as events in other tissues and organs. Moreover, the Snail genes have been the subject of numerous evolutionary studies due to peculiarities such as the evolutionary interchange of the expression patterns of the different Snail genes in different species, and their association with the origin of the neural crest (Sefton et al, 1998;Locascio et al, 2002;Manzanares and Nieto, 2003).…”

Slug (SNAI2) expression in oral SCC cells results in altered cell-cell adhesion and increased motility

“…3,4 Snail homolog 2 (SNAI2), also known as Slug, has been shown to function in a manner similar to that of Snail however Slug displays a distinct tissue distribution. 5,6 During EMT, normally immobile epithelial cells in a tissue detach from neighboring cells and acquire the ability to remodel the extracellular environment and become migratory. This process is required for efficient re-epithelialization of the epidermis in response to wounding and for the migration of neural crest cells during development.…”