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各种指导。神经嵴细胞是如何以如此精确的方式瞄准特定的衍生物和身体部位的？过去20年的研究表明，化学排斥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物的存在仍然是一个有争议的。我们的试点基金表明，躯干神经嵴细胞迁移积极向NRG 1与一组新开发的测定，以研究他们的迁移。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，虽然有大量的研究，管理细胞运动和入侵的过程中的机制，我们没有太多的证据表明，神经嵴细胞经历类似的亚细胞变化，如在癌细胞中看到的。间充质迁移细胞的一个关键步骤是其细胞骨架的极化。细胞在其细胞骨架发生特定变化后会对化学引诱物（或化学排斥物）做出反应（朝向化学引诱物移动），这些变化使细胞骨架中的肌动蛋白和微管蛋白发生变化。拟议的新实验的目标是通过研究一些改变其迁移方向的潜在细胞骨架机制，进一步扩展我们对NRG 1的躯干神经嵴细胞化学吸引力的初步研究结果。 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，管理细胞运动和入侵的过程中的机制，我们没有太多的证据表明，神经嵴细胞经历类似的亚细胞变化，如在癌细胞中看到的。拟议的研究将广泛详细地研究躯干神经嵴肌动蛋白和微管蛋白细胞骨架在NRG 1的化学吸引过程中所经历的变化（极化，动力学和前缘形成）。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，因为它将研究允许神经嵴细胞在整个胚胎中迁移的变化，因为它发生在患有这些癌症的成年人中。

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.