Mechanisms of cytoskeleton dynamics during neural crest cell chemoattraction

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。神经嵴细胞在胚胎发育早期从神经管中出现，并在整个胚胎中迁移。我们刚刚开始了解细胞骨架的变化背后的高运动性和不同的指导。神经嵴细胞如何如此精确地靶向特定的衍生物和身体区域？近20年来的研究表明，化学驱避剂分子在神经嵴迁移中起着至关重要的作用。然而，在神经嵴细胞发育过程中化学引诱剂的存在仍然是一个有争议的问题。我们的试点项目表明，主干神经嵴细胞向NRG1强烈迁移，并采用了一套新开发的方法来研究它们的迁移。有趣的是，神经嵴细胞迁移被反复比作转移和侵袭的过程。然而，尽管对控制细胞运动和侵袭过程的机制进行了大量研究，但我们没有太多证据表明神经嵴细胞经历与癌细胞相似的亚细胞变化。间充质细胞迁移的一个关键步骤是细胞骨架的极化。细胞骨架发生特定变化，使肌动蛋白和微管蛋白细胞骨架极化后，细胞会对化学引诱剂（或化学驱避剂）产生反应（向其移动）。提出的新实验的目标是通过研究一些潜在的细胞骨架机制来进一步扩展我们关于NRG1对干神经嵴细胞化学吸引的初步发现，这些机制改变了它们向定向迁移的方向。

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 neural tube early in embryonic development and migrate throughout the embryo. We are just beginning to understand the cytoskeletal changes underlying their high motility and varied guidance. How do neural crest cells target particular derivatives and body regions with such precision? Research in the past 20 years has shown that chemorepellant molecules play crucial roles in neural crest migration. However, the presence of chemoattractants during neural crest cell development remained a controversial one. Our Pilot grant showed that trunk neural crest cells migrate vigorously towards NRG1 with a set of newly developed assays to study their migration. Interestingly, 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 and invasion, we do not have much evidence showing that neural crest cells undergo similar sub-cellular changes as those seen in cancer cells. One critical step for mesenchymal migratory cells is the polarization of their cytoskeleton. Cells will respond (move towards) to a chemoattractant (or chemorepellant) after undergoing specific changes in their cytoskeleton that allows them to polarize their actin and tubulin cytoskeleton. The goal of the proposed new experiments is to further extend our preliminary findings on trunk neural crest cell chemoattraction by NRG1 by studying some of the underlying cytoskeletal mechanisms that change their migration towards a directional one. 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 and invasion, we do not have much evidence showing that neural crest cells undergo similar sub-cellular changes as those seen in cancer cells. The proposed research will study in extensive detail the changes that trunk neural crest actin and tubulin cytoskeleton undergo (polarizing, dynamics and leading edge formation) during chemoattraction to NRG1. 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 changes that allow neural crest cells migrate throughout the embryo as it happens in adults suffering from these cancers.