Decoding cell states and tissue morphogenesis in the early mammalian embryo

PROJECT SUMMARY/ABSTRACT The overarching goal for this project is to understand the events governing the earliest stages of mammalian embryo development. Specifically, we will investigate how the pluripotent epiblast which generates the embryo- proper, and its sister lineage the extra-embryonic (or primitive) endoderm, arise from a common progenitor population, the inner cell mass. Furthermore, we will determine how the cells of these two nascent lineages differentiate and organize themselves, as they sort into two adjacent tissue layers. We will use the mouse as an experimentally tractable animal model system to investigate a universal and critical stage of mammalian development. We will take an integrative approach across scales (from gleaning molecular details to tissue-level organization) by applying cutting-edge methods, including in toto light microscopic imaging, the analysis of gene expression and protein localization at the level of single cells across a population of cells, as well as performing perturbations, pharmacologic and optogenetic manipulations, within the spatiotemporal context of developing embryos. Our experiments will be coupled to computational analyses of data, and mathematical modeling. These contextual time and space resolved studies will shed insight into how a population of progenitors gives rise to two lineages each possessing a distinct identity and stereotypical tissue organization, and the mechanisms that ensure the robustness reproducibility and scalability of this process. An in-depth mechanistic understanding of critical events taking place in vivo in the mouse model provides the foundational knowledge for: extending our understanding to other mammalian species, the stem cell populations than can be derived from early mammalian embryos which are increasingly being used to generate embryoid (also referred to as synthetic embryo) models, and the differentiation of cells with distinct identities having therapeutic potential. Moreover, using a simple and robust in vivo paradigm of self-organization for decoding the dynamics of cell-cell communication and growth factor signaling will provide insights into how developmental mechanisms are hijacked during disease progression, and can be targeted for therapeutic intervention.