Snail superfamily genes encode zinc finger-containing DNA binding proteins that act as transcriptional repressors. This superfamily has two main branches: the Snail family (encoded by the Snai1, 2 and 3 genes) and the Scratch family (the Scrt1 and 2 genes). These proteins are key regulators of the epithelial- mesenchymal transition, and also play roles in cell proliferation, survival and movement. We have performed a comprehensive genetic analysis of the requirements for Snail superfamily genes during embryonic development in mice. Our work during the prior funding periods of this grant established the null phenotype of all of these genes, and demonstrated that the most severe embryonic phenotype is observed in Snai1 mutants. However, many questions remain about the requirements and roles of Snail superfamily genes. In this proposal, both molecular and genetic approaches will be utilized to analyze the roles played by Snail family genes during embryogenesis in mice, and to understand the mechanisms causing the mutant phenotypes. The mutant mouse strains we have already generated, as well as the mutant strains we will construct as part of this proposal, constitute a unique set of reagents that will permit us to finely dissect the roles of Snail family genes during embryonic development.
The specific aims of this proposal are: 1) determine targets for transcriptional repression by the SNAI1 protein during early embryogenesis in mice;2) test the hypothesis that post- translational regulation of SNAI1 protein by the GSK3beta kinase and the betaTrcp ubiquitin ligase are essential for Snai1 function in vivo;3) test the hypothesis that Snail family genes are important for muscle development, physiology and regeneration by determining the individual roles of the Snai1, Snai2 and Snai3 genes in these processes;4) assess Snai3 redundancy with Snai2 and Snai1 function during muscle development, physiology and regeneration. Public Health Relevance: The long-term goal of this proposal is to understand the roles that Snail superfamily genes play during embryonic development in mammals. Snail superfamily genes encode zinc finger-containing DNA binding proteins that act as transcriptional repressors. The studies described in this proposal will further our understanding of the roles played by Snail superfamily genes during mammalian development, and will be relevant to the study of both normal and abnormal human development.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD034883-16
Application #
8302414
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Coulombe, James N
Project Start
1998-01-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
16
Fiscal Year
2012
Total Cost
$321,056
Indirect Cost
$115,909
Name
Maine Medical Center
Department
Type
DUNS #
071732663
City
Portland
State
ME
Country
United States
Zip Code
04102
Chen, Ying; Gridley, Thomas (2013) Compensatory regulation of the Snai1 and Snai2 genes during chondrogenesis. J Bone Miner Res 28:1412-21
Chen, Ying; Gridley, Thomas (2013) The SNAI1 and SNAI2 proteins occupy their own and each other's promoter during chondrogenesis. Biochem Biophys Res Commun 435:356-60
Xu, Jingxia; Gridley, Thomas (2013) Notch2 is required in somatic cells for breakdown of ovarian germ-cell nests and formation of primordial follicles. BMC Biol 11:13
Batlle, R; Alba-Castellon, L; Loubat-Casanovas, J et al. (2013) Snail1 controls TGF-ýý responsiveness and differentiation of mesenchymal stem cells. Oncogene 32:3381-9
Bradley, Cara K; Norton, Christine R; Chen, Ying et al. (2013) The snail family gene snai3 is not essential for embryogenesis in mice. PLoS One 8:e65344
Boucher, Joshua; Gridley, Thomas; Liaw, Lucy (2012) Molecular pathways of notch signaling in vascular smooth muscle cells. Front Physiol 3:81
Krebs, Luke T; Bradley, Cara K; Norton, Christine R et al. (2012) The Notch-regulated ankyrin repeat protein is required for proper anterior-posterior somite patterning in mice. Genesis 50:366-74
Tao, Ge; Levay, Agata K; Gridley, Thomas et al. (2011) Mmp15 is a direct target of Snai1 during endothelial to mesenchymal transformation and endocardial cushion development. Dev Biol 359:209-21
Varnum-Finney, Barbara; Halasz, Lia M; Sun, Mingyi et al. (2011) Notch2 governs the rate of generation of mouse long- and short-term repopulating stem cells. J Clin Invest 121:1207-16
Feng, Xuesong; Krebs, Luke T; Gridley, Thomas (2010) Patent ductus arteriosus in mice with smooth muscle-specific Jag1 deletion. Development 137:4191-9

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