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。神经嵴细胞在发育中从神经上皮中出现并转化为间充质/迁移群体。几种抑制性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Slit 1-3。Slit分子最初是作为轴突导向分子被发现的;然而，最近它们也被证明是真正的肿瘤抑制因子，并影响癌细胞中的细胞增殖。神经嵴细胞迁移被反复比作癌症转移和细胞侵袭的过程。Slit分子通过调节β-连环蛋白表达来减弱癌症进展，并且还能够负调节转移。我们以前的研究结果表明，Slit化学排斥分子损害神经嵴细胞迁移，并改变神经嵴细胞的细胞骨架组织向非迁移表型。然而，我们仍然不知道Slit分子在迁移前神经嵴细胞中发挥的确切作用。做 狭缝分子防止神经嵴分层的方式类似于狭缝防止肿瘤转移？如果是这样的话，是什么样的分子机制使Slit分子能够防止迁移前神经嵴细胞的分层？裂隙调节迁移前神经嵴细胞增殖吗？该提议的意义在于，它将确定Slits是否通过其“肿瘤抑制机制”在上皮-间充质转化（EMT）期间对神经嵴分层具有影响和/或Slits是否调节迁移前神经嵴增殖。这一新建议的方法是研究 的Slit分子在迁移前的神经嵴细胞使用细胞生物学和基因组学方法。该项目的研究结果将：1）扩大目前对肿瘤抑制因子Slits在神经嵴细胞增殖中作用的认识; 2）确定迁移前神经嵴细胞是否需要在分层前沉默Slits;以及3）通过阐明Slits在细胞迁移中的作用来深入了解肿瘤抑制因子活性。

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.