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

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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.