Understanding how PAR proteins cooperate to establish cell polarity (New Investigator)

为了从一个最初对称的单细胞胚胎生成生物体，细胞分裂并失去其最初的对称性，通过称为细胞极化的过程获得结构和功能上的差异。动物细胞极化的一个关键步骤是保守极性效应分布到细胞表面的离散域。从它们的不对称位置，这些关键蛋白质控制着构建生物体的重要事件，包括所需的大量细胞类型的产生，组织成器官的组织以及奠定动物结构计划基础的胚胎轴的建立。因此，当这些极性效应物的位置和功能受损时，可以产生包括癌症在内的各种疾病。是什么保证了这些极性蛋白的正确定位和功能？我们最近发现了一种调节这些极性效应的新方法。我们发现，就像在制造工厂里一样，极性蛋白质有一个分工，它将指定一个细胞结构域。它们将自己组合成不同的蛋白质复合物，这些蛋白质复合物专门用于特定的功能。对于我们研究的蛋白质，我们发现至少有两种不同的蛋白质复合物，一种专门研究极性蛋白质的不对称分布，另一种专注于它们的激活。这些蛋白质复合物之间需要非常紧密的功能协调，以产生不对称的和活跃的极性蛋白域，使细胞极化，从而允许生物体的发育。我们不知道这种重要的合作是如何实现的；因此，我们提出创新的细胞生物学技术，以确定所涉及的球员和他们的行动模式。通过了解细胞如何极化，我们将深入了解人类胚胎发育的关键方面，我们将查明可能出错并导致疾病的事件。因此，我们确定控制正确细胞极化的机制是很重要的；从长远来看，理解这一点将为药物设计提供新的途径，从而纠正这些控制机制中的错误。

To generate an organism from an initially symmetric one-cell embryo, cells divide and lose their initial symmetry, acquiring structural and functional differences through a process termed cell polarisation. A crucial step in the polarisation of animal cells is the distribution of conserved polarity effectors to discrete domains on the cell surface. From their asymmetric position these key proteins control important events that build an organism, including the generation of the plethora of cell types needed, the organization of tissues into organs and the establishment of embryonic axes that lay the bases for the architectural plan of an animal. Therefore, when the position and function of these polarity effectors is impaired a wide range of diseases can arise including cancer. What ensures the correct localisation and function of these polarity proteins? We recently identified a new way of regulation for these polarity effectors. We found that, like in a manufacturing factory, there is a division of labour for the polarity proteins that will specify a cell domain. They group themselves into distinct protein-complexes, which become specialised in a given function. For the proteins we studied we found that there are at least two distinct protein-complexes, one specialised in the asymmetric distribution of the polarity proteins and the other focused on their activation. A very tight functional coordination between these protein-complexes is required to generate an asymmetric and active domain of polarity proteins that will polarise cells, allowing the development of an organism. We do not know how this important cooperation is achieved; therefore we propose innovative cell biology techniques to identify the players involved and their modes of action. By understanding how cells are polarised we will give insight into key aspects of human embryo development and we will pinpoint events that can go wrong and cause disease. Thus it is important that we identify the mechanisms that control correct cell polarisation; understanding this will, in the long-term, provide new avenues in the design of drugs that can correct errors in these mechanisms of control.