Squeezing through the embryo:Dissecting nuclear mechanics during embryonic cell migration

巨噬细胞是高度能动的免疫细胞，通常是抵御病原体的第一道防线。它们还有助于伤口愈合和清除死亡细胞和碎片，以及组织重建。所有这些功能对于确保动物的准确发育和成年动物的动态平衡是极其重要的。它们也可以被重新编程，以极其有害的方式发挥作用，帮助癌症转移和加剧炎症。由于巨噬细胞的迁移能力是其准确发挥功能的基础，因此了解巨噬细胞的迁移对我们确保一生中健康生活的能力具有重要意义。我们以常见果蝇的巨噬细胞为模型系统来研究巨噬细胞的迁移。果蝇巨噬细胞，也称为血细胞，与脊椎动物非常相似；它们具有相似的起源，并利用相似的机制进行迁移。我们最近在胚胎中使用果蝇巨噬细胞的工作表明，它们可以挤压到非常密集的组织环境中，这种在严格限制下迁移的能力对于确保巨噬细胞在胚胎中的分布很重要。在这项提案中，我们讨论了巨噬细胞核通过组织屏障移动的机制。作为遗传信息储存库的细胞核恰好也是细胞中最坚硬的细胞器。因此，通过障碍物移动原子核并不是一件容易的事情，而原子核形变是禁闭下迁移的关键。我们最近发现，当巨噬细胞核通过胚胎时，它们在形状上经历了广泛的重排。利用生物物理和遗传学实验以及尖端图像分析和数学建模相结合的方法，我们试图了解产生和转换的机械力，以使细胞核变形和移动。我们还试图了解核变形如何反过来影响基因表达，从而影响巨噬细胞的功能。我们预计，支配核机制的基本原理将在多种细胞类型中保守，我们的建议的结果不仅将为巨噬细胞迁移的研究提供信息，还将为其他胚胎迁移细胞类型甚至转移癌细胞的研究提供信息。

Macrophages are highly motile immune cells which often act as the first line of defence against pathogens. They also assist in wound healing and clearing up of dead cells and debris and tissue remodelling. All these functions are extremely important to ensure accurate animal development and homeostasis in the adult. They can also be reprogrammed to act in highly detrimental ways, assisting cancer metastasis and exacerbating inflammation. Since their ability to migrate underpins their ability to function accurately, understanding macrophage migration has important implications to our ability to ensure healthy living across the lifespan. We use the macrophages of the common fruit fly Drosophila Melanogaster as a model system to study macrophage migration. Fruit fly macrophages, also called haemocytes, are very like their vertebrate counterparts; they display similar origins and utilize similar mechanisms to migrate. Our recent work using the fruit fly macrophages in the embryo showed that they can squeeze into very dense tissue environments and this ability to migrate under tight confinement is important to ensure macrophage distribution within the embryo. In this proposal, we address the mechanisms through which the macrophage nucleus is moved through tissue barriers. The nucleus which is the repository of the genetic information also happens to be the stiffest organelle in the cell. Hence, moving the nucleus through barriers is not an easy task and nuclear deformation is key to migration under confinement. We have recently discovered that the macrophage nucleus undergoes extensive rearrangements in shape while they move through the embryo. Using a combination of biophysical and genetic experiments as well as cutting edge image analysis and mathematical modelling, we seek to understand the mechanical forces which are generated and transduced to deform and move the nucleus. We also seek to understand how nuclear deformations can in turn affect gene expression and thus macrophage functionality. We anticipate that fundamental principles which govern nuclear mechanics will be conserved across multiple cell types and the results of our proposal will inform studies not only on macrophage migration, but that of other embryonically migrating cell types and even metastatic cancer cells.