Regulation of Cell Migration in Development

描述(申请人提供)：细胞迁移是胚胎发育、伤口愈合和肿瘤转移的主要驱动力。因此，了解控制细胞是否移动、何时移动以及移动到哪里的分子机制对人类健康和疾病具有重要意义。我的实验室已经开发了一个相对简单和遗传上容易处理的模型，用于研究细胞运动的发育调节，即果蝇卵巢中被称为边界细胞的一小群细胞的运动。我们已经确定了类固醇激素、细胞因子和生长因子信号通路，它们是边界细胞迁移的空间和时间调节所必需的。在之前的资助阶段，我们发现类固醇激素和细胞因子信号的整合控制着边缘细胞迁移的发育时间。我们发现，通过JAK/STAT通路的持续信号不仅是为了最初确定迁徙人口，也是为了在整个迁徙过程中保持运动性。我们取得了重大进展，首次成功地对边界细胞迁移进行了时间推移的实时成像。实时成像揭示了一些在固定样本中不明显的现象，包括从上皮分离的过程是漫长、缓慢的，在分子水平上可能是复杂的。为了让细胞分离，我们发现必须在将迁移的细胞和不会迁移的细胞之间做出明确的细胞命运区分。在对影响边缘细胞发育和迁移的突变体的遗传筛选中，我们发现无核基因在这一区别中起着关键作用。我们进一步发现，Apontic作为JAK/STAT信号的反馈抑制因子，限制了迁移种群，我们为这个过程开发了一个数学模型和计算机模拟，忠实地再现了野生型和突变的条件。在我们的第一个特定目标中，我们建议测试我们的模型对APT功能的特定预测，以及它与SLBO和STAT的相互作用。在目标2和目标3中，我们建议分别研究脱离和定向引导过程背后的分子机制。总而言之，这些研究应该会显著促进我们对控制集体细胞运动的机制的理解，我们认为集体细胞运动与控制单个细胞的机制有很大不同。与公共健康相关：移动能力是几乎所有动物的细胞的特性，从简单的苍蝇和蠕虫，一直到人类。这项拟议中的研究重点是果蝇中一小群细胞的运动，以了解更多关于特定分子如何在何时、何地和如何运动的信息。由于细胞运动有助于伤口愈合和肿瘤转移，这些研究可能导致发现新的药物靶点，可以促进愈合或抑制癌细胞的扩散。

DESCRIPTION (provided by applicant): Cell migration is a major driving force in embryonic development, wound healing, and tumor metastasis. Therefore understanding the molecular mechanisms that control whether, when, and where cells move is significant for human health and disease. My laboratory has developed a relatively simple and genetically tractable model for the study of the developmental regulation of cell motility, the movement of a small group of cells in the Drosophila ovary known as the border cells. We have identified steroid hormone, cytokine and growth factor signaling pathways that are required for the spatial and temporal regulation of border cell migration. In the previous funding period we showed that integration of steroid hormone and cytokine signaling governs the developmental timing of border cell migration. We found that continuous signaling through the JAK/STAT pathway is required not only to specify the migratory population initially, but also to sustain motility throughout their migration. We made a significant advance by succeeding for the first time in time-lapse, live- imaging of border cell migration. Live-imaging has revealed several phenomena that were not evident in fixed samples, including that the process of detachment from the epithelium is long, slow and likely complex at the molecular level. For the cells to detach, we find that a sharp cell fate distinction must be made between cells that will migrate and those that will not. In a genetic screen for mutants that affect border cell development and migration, we identified the gene apontic as playing a critical role in this distinction. We further discovered that Apontic functions as a feedback inhibitor of JAK/STAT signaling that limits the migratory population, a process for which we developed a mathematical model and computer simulations that faithfully reproduce wild-type and mutant conditions. In our first specific aim we propose to test specific predictions of our model for Apt function and its interactions with SLBO and STAT. In aims 2 and 3, we propose to investigate the molecular mechanisms underlying the processes of detachment and directional guidance, respectively. Together these studies should significantly advance our understanding of the mechanisms that control collective cell movements, which we propose differ significantly from those controlling individual cells. PUBLIC HEALTH RELEVANCE: The ability to move is a property of cells from virtually all animals, from simple ones such as flies and worms, all the way to humans. The proposed research focuses on the movement of a small group of cells in the fruit fly, to learn more about how specific molecules orchestrate when, where and how they move. Since cell motility contributes to wound healing and tumor metastasis, these studies could lead to the discovery of new drug targets that could promote healing or inhibit the spread of cancer cells.