Role of Slit molecules in neural crest delamination

描述（由申请人提供）：神经嵴提供了一个独特的迁移干细胞群，用于研究各种细胞和神经发育过程。神经嵴细胞在发育过程中从神经上皮中出现，并转化为间充质/迁移群体。一些抑制分子已被证明在神经嵴迁移中起重要作用，包括化学排斥分子狭缝1-3。狭缝分子最初是作为轴突引导分子发现的；然而，最近它们也被证明是真正的肿瘤抑制因子，并影响癌细胞的细胞增殖。神经嵴细胞迁移已多次被比作癌症转移和细胞侵袭的过程。狭缝分子通过调节β -连环蛋白的表达来减缓癌症的进展，也能够负性地调节转移。我们之前的研究结果表明，狭缝化学驱避分子损害神经嵴细胞的迁移，并改变神经嵴细胞的细胞骨架组织，使其向非迁移表型转变。然而，我们仍然不知道狭缝分子在迁移前神经嵴细胞中的确切作用。做

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; however, recently they have been also shown to be true tumor suppressors and affect cell proliferation in cancer cells. 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? Do Slits modulate pre-migratory neural crest cell proliferation? The significance of this proposal is that it will determne whether or not Slits have an effect on neural crest delamination during the epithelial-to- mesenchymal transition (EMT) via their "tumor suppressor mechanisms" and/or if Slits modulate pre-migratory neural crest proliferation. The approach of this new proposal is to study of the role of Slit molecules in the pre-migratory neural crest cell 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 cell proliferation; 2) determine if pre-migratory neural crest cels need to silence Slits before delamination; and, 3) provide insight into tumor suppressor activity by elucidating the role of Slits in cell migration.