Understanding the mechanisms of aneuploid cell elimination during early mammalian development

在早期发育过程中，细胞分裂中的错误会导致子细胞的染色体数量减少或增加。这种情况被称为非整倍体，对胚胎发育非常有害。在发育过程中，非整倍体细胞通常通过质量控制机制从胚胎中移除，以确保组织的适应性。当这是不可能的非整倍体导致流产。然而，尽管非整倍体是人类自然流产的主要原因，我们仍然对胚胎发育过程中染色体异常的后果知之甚少。在这个提议中，我们的目标是确定在哺乳动物早期发育过程中非整倍体细胞发生了什么。为此，我们将做三件事：首先，我们将分析非整倍体细胞在早期胚胎发育过程中最重要的特性。为了实现这一目标，我们将使用小鼠胚胎作为我们的模型系统，因为它的早期发展概括了人类发展的许多特征。利用这个系统，我们将在细胞和胚胎中人工诱导非整倍体，并分析在这些细胞中激活了哪些类型的应激途径。一旦非整倍体诱导的特定应激途径被确定，这些将被操纵来测试激活是否再现非整倍体的不利影响。我们还将测试抑制这些压力是否会阻止胚胎中非整倍体细胞的消除。为了研究非整倍体细胞在发育过程中发生了什么，我们要做的第二件事是分析哪些信号被非整倍体诱导的应激激活并导致非整倍体细胞和胚胎的死亡。我们之前的工作已经确定了mTOR通路，这是细胞生长的关键调节因子，对于消除胚胎发育过程中的异常细胞同样重要。在这里，我们将通过询问其抑制如何阻止非整倍体细胞繁殖来测试mTOR途径对消除非整倍体细胞的重要性。我们在胚胎发生过程中研究非整倍性的第三件事是准确分析在胚胎发育过程中非整倍体细胞何时被消除。为此，我们将研究小鼠胚胎发生不同阶段的非整倍体水平。我们预计，我们的研究将提供一个全面的概述，什么命运的非整倍体是在胚胎和什么是非整倍体的不利影响。

During early development errors in cell division causes the daughter cells to have either fewer or extra numbers of chromosomes. This condition is called aneuploidy and is highly detrimental to embryogenesis. During development, aneuploid cells are normally removed from the embryo by the quality control mechanisms that ensure tissue fitness. When this is not possible aneuploidy causes miscarriage. However, in spite of aneuploidy being the leading cause of spontaneous pregnancy loss in humans, we still know surprisingly little about the consequences of chromosomal abnormalities during embryonic development.In this proposal we aim to identify what happens to aneuploid cells during early mammalian development. For this we will do three things:First, we will analyse which are the most important properties of aneuploid cells during early embryo development. To achieve this, we will use the mouse embryo as our model system as its early development recapitulates many features of human development. Using this system, we will artificially induce aneuploidy in cells and embryos and analyse what types of stress pathways are activated in these cells. Once the specific stress pathways that are induced by aneuploidy are identified, these will manipulated to test if activation reproduces the adverse effects of aneuploidy. We will also test if inhibiting these stresses prevents aneuploid cell elimination in the embryo.The second thing that we will do to study what happens to aneuploid cells during development is to analyse what signals are activated by aneuploidy induced stress and cause the death of aneuploid cells and embryos. Our previous work has identified the mTOR pathway, that is a key regulator of cell growth, as important for the elimination of abnormal cells during embryonic development. Here we will test the importance of the mTOR pathway for the elimination of aneuploid cells by asking how its repression prevents aneuploid cell propagation.The third thing that we will do to study aneuploidy during embryogenesis is to analyse exactly when aneuploid cells are eliminated during embryo development. For this we will study the levels of aneuploidy at different stages of mouse embryogenesis.Together we anticipate that our studies will provide a comprehensive overview of what the fate of aneuploidy is in the embryo and what are the adverse effects of aneuploidy.