Role of Slit molecules in neural crest delamination

California State University Northridge, Northridge CA

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Abstract

DESCRIPTION (provided by applicant): The neural crest provides a unique population of migratory stem cells with which to study a variety of cell and neural developmental processes. Neural crest cells emerge from the neuroepithelium in development and transform into a mesenchymal/migratory population. Several inhibitory molecules have been shown to play important roles in neural crest migration including the chemorepulsive molecules Slit 1-3. Slit molecules were initially discovered as axonal guidance molecules and the cartoon below depicts what is currently known about the expression of Slit chemorepellants, the expression of Slit receptors (Robo) and their effect on neural crest migration. Neural crest cell migration has been repeatedly likened to the process of cancer metastasis and cell invasion. Slit molecules attenuate cancer progression by regulating beta-catenin expression and are also able to negatively regulate metastasis. Results from our previous grant demonstrated that Slit chemorepellant molecules impair neural crest cell migration and alters neural crest cells cytoskeletal organization towards a non-migratory phenotype. However, we still do not know the precise role that Slit molecules play on pre-migratory neural crest cells. Do Slit molecules prevent neural crest delamination in a manner analogous to the way Slits prevent tumor metastasis? If so, what are the molecular mechanisms that allow Slit molecules to prevent the delamination of the pre- migratory neural crest cells? The significance of this proposal is that it will determine whether or not Slits have an effect on neural crest delamination during the epithelial-to- mesenchymal transition (EMT) via their "tumor suppressor mechanisms". The approach of this new proposal is to study of the role of Slit molecules in neural crest cell delamination using cell biology and genomic methods. The findings from this project will: 1) expand the current knowledge on the role of the tumor suppressor Slits in neural crest migration;2) determine if neural crest cells expressing Slits are unable to delaminate;and, 3) provide insight into tumor suppressor activity by elucidating the role of Slits in cell migration. Public Health Relevance Statement: The outcomes from this research will help us understand how we may be able to harness the metastatic aggressiveness of crest derived-cancers because it will look into the role that a tumor suppressor molecule, Slit, have on its progenitor population and correlate it with cancer aggressiveness. PUBLIC HEALTH RELEVANCE: Neural crest cell migration has been repeatedly likened to the process of metastasis and invasion. However, although there is a wealth of research on the mechanisms that govern the process of cell motility of neural crest cells we still do not know the precise role that Slit molecules play on pre-migratory neural crest cells. The proposed research will study the role of Slit molecules in neural crest cell delamination using cell biology and genomic methods. The outcomes from this research will enhance our understanding of how Slit molecules affect the EMT process of neural crest migration and will determine if these processes are similar to the processes occurring when tumor cells become metastatic.