Role of Slit molecules in neural crest delamination

描述(由申请人提供)：神经脊提供了一个独特的迁移干细胞群体，用来研究各种细胞和神经发育过程。神经脊细胞在发育过程中从神经上皮细胞分化为间充质/迁徙细胞群。一些抑制分子已被证明在神经脊迁移中发挥重要作用，包括化学斥力分子Sit1-3。狭缝分子最初被发现是轴突导向分子；然而，最近也被证明它们是真正的肿瘤抑制因子，并影响癌细胞的细胞增殖。神经脊细胞的迁移被反复地比作癌症转移和细胞侵袭的过程。Sit分子通过调节β-连环蛋白的表达来减缓癌症的进展，并能够负向调节转移。我们先前资助的结果表明，SILT化学排斥剂分子损害了神经脊细胞的迁移，并改变了神经脊细胞的细胞骨架组织，使其向非迁移性表型转变。然而，我们仍然不知道缝隙分子在迁移前神经脊细胞中所起的确切作用。做 狭缝分子防止神经脊分层的方式类似于狭缝防止肿瘤转移的方式？如果是这样的话，是什么分子机制使缝隙分子能够防止迁移前神经脊细胞的分层？狭缝是否调节迁移前神经脊细胞的增殖？这一建议的意义在于，它将决定SIts是否通过其“肿瘤抑制机制”影响上皮向间充质转化(EMT)过程中神经脊的剥离和/或SIts是否调节迁移前神经脊的增殖。这一新建议的方法是研究 使用细胞生物学和基因组学方法对迁移前神经脊细胞中的缝隙分子进行研究。该项目的发现将：1)扩大目前关于肿瘤抑制因子Slits在神经脊细胞增殖中的作用的知识；2)确定迁移前的神经脊干细胞是否需要在分层之前抑制Sits；以及3)通过阐明Slits在细胞迁移中的作用，提供对肿瘤抑制活性的洞察。

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.