GSK3 and lamellipodial dynamics in migrating neural crest cells

在人体发育和日常生物过程中，细胞运动是极其重要的。此外，在伤口愈合和更换老化组织时，细胞运动变得至关重要。最后，细胞运动会影响癌细胞在体内扩散的程度。这是一个很难研究的过程，因为当细胞四处移动时，很难看到活体内的情况。在这项提议中，我们使用一种名为神经脊的胚胎细胞群来研究细胞如何接收和解释来自环境的信号。神经脊是一个非常有趣的细胞群，对人类的各种组织都有贡献，包括头骨、神经、色素和脂肪。尽管这些细胞变得非常不同，但它们都出生在神经板边缘的胚胎中。然后，它们必须从神经管中出来，在体内迁移，在某些情况下，在定居之前要经过很长的距离。例如，控制肠道运动的神经必须移动到肠道，同时正确地成为神经。当这种情况发生时，肠道就不能正常工作，从而导致先天性巨结肠。由于神经脊细胞在分化前在全身传播，它们是少数几个与转移瘤细胞最相似的正常细胞群之一。事实上，神经脊细胞有时会在晚年重新激活，然后形成高侵袭性的癌症，如黑色素瘤、神经母细胞瘤和胶质母细胞瘤。在这个项目中，我们正在研究驱动这些细胞运动的机制。我们已经确定了几种帮助细胞向前移动的蛋白质，但它们形成了一个广泛的“脚状”结构，可以在周围组织中摸索前进。我们想问的是，当这些蛋白质无法发挥作用时会发生什么。问题包括：细胞能否伸展并朝着正确的方向移动，它们能否通过使用另一种运输方式进行补偿，它们仍能如此快速地移动吗？这些问题的答案对于我们理解胚胎中的组织是如何聚集在一起并形成器官将是重要的。我们还将学习当这个过程出错时会发生什么(例如，这是否会导致出生缺陷)，以及让我们深入了解癌细胞如何在体内移动。

Cell movement is extremely important during development of the human body and during every day biological processes. In addition, cell movements become critically necessary during wound healing and when replacing aging tissues. Finally, cell movements influence how far cancer cells can spread in the body. This is a process that is very difficult to study because it is hard to see inside the live body as cells move around. In this proposal, we use an embryonic cell population called the neural crest to study how cells receive and interpret signals from the environment.The neural crest is a very interesting cell population which contributes to all kinds of tissues in humans, including bones of the head, nerves, pigmentation and fat. Although these cells become very different, they are all born in the embryo at the edge of the neural plate. They then have to emerge from the neural tube and migrate through the body, in some cases travelling great distances before settling down. For example, the nerves that control bowel movements must travel to the gut, while correctly becoming nerves. When this goes wrong, the bowels don't work, resulting in Hirschsprung's disease. Because neural crest cells travel throughout the body before they differentiate, they are one of the few normal cell populations that are most similar to metastatic tumour cells. In fact, the neural crest cells sometimes reactivate in later life, and can then form highly invasive cancers such as melanoma, neuroblastoma and glioblastoma.In this project, we are studying the machinery that drives the movement of these cells. We have identified several proteins help the cells to move in a forward direction, but making a broad "footlike" structure that feels its way through surrounding tissues. We want to ask what happens when these proteins are unable to function. Questions include: can the cells reach out and move in the correct direction, can they compensate by using another method of transportation, can they still move as quickly? The answers to these questions will be important for our understanding of how the tissues in the embryo come together and make organs. We will also learn what happens when the process goes wrong (for example, does this cause birth defects) as well as giving us insight into how cancer cells move through the body.