Investigating the role of ASPP2 in post-implantation mouse embryos - WCUB, ENWW

该项目将重点关注ASPP 2在植入后胚胎中的作用。该基因对胚胎发生至关重要，当被敲除时，会在着床后的早期阶段导致胚胎死亡。ASPP 2的关键功能之一是调节关键转录效应子雅普。当有活性时，雅普以其去磷酸化形式存在于细胞核中，在那里它与转录因子如TEAD 4结合，并导致参与细胞增殖、分化和凋亡的基因的表达。ASPP 2与雅普和磷酸酶PP 1在植入后胚胎的紧密连接处形成复合物，其能够去磷酸化并因此激活雅普。还发现ASPP 2在上皮细胞和中枢神经系统的紧密连接处与PAR-3相互作用，在建立和维持极性方面发挥作用。因此，ASPP 2涉及几个重要的细胞过程，但目前尚不清楚ASPP 2是否也调节植入后胚胎的极性。我将研究ASPP 2在植入后胚胎中的作用，以深入了解其功能和作用机制。我将首先研究它在着床后发育中的作用，以推断它在胚胎发生中的重要性。然后，我将更深入地研究它的作用机制，因为，由于ASPP 2和雅普都可能参与广泛的关键细胞活动，ASPP 2功能的分子基础可能适用于许多不同的情况。例如，极性的建立和细胞增殖的控制对于组织的稳态是必不可少的，如果这些过程中的任何一个出错，都可能导致癌症。此外，ASPP 2可能作为极性和细胞增殖/分化之间的联系，因此该项目的发现可能提供对组织力学的见解。BBSRC优先领域：已经在上皮细胞中显示ASPP 2在建立极性和调节雅普活性中起作用，但是目前尚不清楚它是否在胚胎发生中起这种作用。ASPP 2和雅普在胚胎发生中的研究将阐明细胞分化、增殖和极性的机制--胚胎中发生的三个关键细胞过程受这两种蛋白质的调控。在更广泛的背景下，这些过程对于组织的正常功能也至关重要，其中任何一个过程的破坏通常都会导致癌症等疾病。例如，极性的建立和维持对于组织内稳态至关重要。在癌症的情况下，细胞表现出极性丧失和过度增殖的趋势。由于ASPP 2是一种已知的肿瘤抑制因子，并已被发现在建立极性中发挥作用，因此了解ASPP 2作用的分子机制将提供可用于改善人类和动物健康的知识，后者是BBSRC的优先领域之一。

This project will focus on the role of ASPP2 in post-implantation embryos. This gene is crucial for embryogenesis, causing embryonic lethality at an early stage post-implantation when knocked out. One of the key functions of ASPP2 is to regulate key transcriptional effector YAP. When active, YAP is found in the nuclei of cells in its dephosphorylated form, where it binds to transcription factors, such as TEAD4, and leads to expression of genes involved in cell proliferation, differentiation and apoptosis. ASPP2 forms a complex at tight junctions in post-implantation embryos with YAP and phosphatase PP1, which is able to dephosphorylate and so activate YAP. ASPP2 has also been found to interact with PAR-3 at tight junctions in epithelial cells and in the central nervous system, playing a role in establishing and maintaining polarity. Thus ASPP2 is implicated in several important cellular processes but it is currently unknown whether ASPP2 also regulates polarity in post-implantation embryos. I will be studying the role of ASPP2 in post-implantation embryos in order to gain insight into its functions and the mechanisms by which it acts. I will be looking firstly at its role in post-implantation development in order to deduce its importance in embryogenesis. I will then study the mechanisms by which it acts in more depth, because, due to the wide range of key cellular activities that both ASPP2 and YAP may be involved in, the molecular basis of ASPP2's function may be applicable to many diverse situations. For example, establishment of polarity and control of cell proliferation are essential for tissue homeostasis and may result in cancer if either of these processes go awry. In addition, ASPP2 may act as a link between polarity and cell proliferation/differentiation, thus the findings from this project may provide insight into tissue mechanics. BBSRC priority areas: It has been shown in epithelial cells that ASPP2 plays a role in both establishing polarity and regulating YAP activity but it is currently unknown whether it plays this role in embryogenesis. The study of ASPP2 and YAP in embryogenesis will shed light on the mechanisms involved in cell differentiation, proliferation and polarity - three key cellular processes occurring in embryos that are regulated by these two proteins. In a broader context, these processes are also crucial for the normal functioning of tissues and disruption of any one of these generally leads to diseases such as cancer. The establishment and maintenance of polarity, for example, is critical for tissue homeostasis. In the case of cancer, cells exhibit a loss of polarity and a tendency to over-proliferate. As ASPP2 is a known tumour suppressor and has been found to play a role in establishing polarity, understanding the molecular mechanisms by which ASPP2 acts will provide knowledge that could be used to improve the health of humans and animals, the latter of which is one of BBSRC's priority areas.