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。狭缝分子最初是作为轴突引导分子被发现的，下面的卡通画描绘了目前已知的关于狭缝化学反应物的表达、狭缝受体(ROBO)的表达及其对神经脊迁移的影响。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。狭缝分子是否以类似于狭缝分子防止肿瘤转移的方式来防止神经脊分层？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？这一建议的意义在于，它将确定在上皮向间充质转化(EMT)过程中，SLITS是否通过其“肿瘤抑制机制”对神经脊剥离产生影响。这一新建议的方法是利用细胞生物学和基因组学方法研究缝隙分子在神经脊细胞分层中的作用。该项目的发现将：1)扩大目前关于肿瘤抑制因子Sits在神经脊迁移中的作用的知识；2)确定表达Sits的神经脊细胞是否不能分层；以及3)通过阐明Sits在细胞迁移中的作用，提供对肿瘤抑制活性的洞察。公共卫生相关性声明：这项研究的结果将有助于我们了解如何利用CREST来源的癌症的转移侵袭性，因为它将研究肿瘤抑制分子SIIT对其祖细胞群体的作用，并将其与癌症侵袭性相关联。 公共卫生相关性：神经脊细胞迁移已多次被比作转移和侵袭的过程。然而，尽管已经有大量关于神经脊细胞运动过程的机制的研究，但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。这项拟议的研究将利用细胞生物学和基因组学方法研究缝隙分子在神经脊细胞分层中的作用。这项研究的结果将加深我们对狭缝分子如何影响神经脊迁移的EMT过程的理解，并将确定这些过程是否类似于肿瘤细胞转移时发生的过程。

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.