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分子最初被发现为轴突导向分子，下面的漫画描述了目前已知的关于Slit化学排斥剂的表达、Slit受体（Robo）的表达及其对神经嵴迁移的影响。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。从我们以前的资助结果表明，狭缝化学排斥分子损害神经嵴细胞迁移和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。Slit分子是否以类似于Slit防止肿瘤转移的方式防止神经嵴分层？如果是的话，是什么样的分子机制使Slit分子能够阻止迁移前神经嵴细胞的分层？这一提议的意义在于，它将确定在上皮-间充质转化（EMT）期间，裂缝是否通过其“肿瘤抑制机制”对神经嵴分层具有影响。本研究的目的是利用细胞生物学和基因组学方法研究Slit分子在神经嵴细胞脱层中的作用。该项目的研究结果将：1）扩大目前对肿瘤抑制因子Slits在神经嵴迁移中作用的认识; 2）确定表达Slits的神经嵴细胞是否无法分层; 3）通过阐明Slits在细胞迁移中的作用，提供对肿瘤抑制因子活性的深入了解。公共卫生相关性声明：这项研究的结果将帮助我们了解我们如何能够利用嵴源性癌症的转移侵袭性，因为它将研究肿瘤抑制分子Slit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：神经嵴细胞迁移被反复比作转移和侵袭的过程。然而，虽然有大量的研究机制，支配神经嵴细胞的细胞运动的过程中，我们仍然不知道确切的作用，Slit分子在迁移前的神经嵴细胞。这项研究将利用细胞生物学和基因组学方法研究Slit分子在神经嵴细胞分层中的作用。这项研究的结果将增强我们对Slit分子如何影响神经嵴迁移的EMT过程的了解，并将确定这些过程是否与肿瘤细胞转移时发生的过程相似。

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.