The gut endoderm is the precursor tissue of the respiratory and digestive tracts, and their associated visceral organs. In this project we will use a suite of state-of-the-art technologies to address fundamental questions focused on mechanisms of mammalian gut endoderm cell lineage commitment and tissue morphogenesis, as well as probing the developmental origin and fate of cells that comprise the gut endoderm, using the mouse model. Our previous studies have provided a paradigm-shift in our understanding of the origin and mechanism of formation of the gut endoderm. Using fate mapping, live imaging and more recently single-cell transcriptomic methods, we demonstrated that the gut endoderm of mice comprises cells of two distinct developmental origins; embryonic definitive endoderm, and extra-embryonic visceral endoderm. The dual origin of the gut endoderm challenges the prevailing view of germ layer formation in mammals which posits that endoderm, along with mesoderm and ectoderm, derives solely from pluripotent epiblast. We have also shown that the gut endoderm forms through a novel intercalation mechanism and identified SOX17 as a critical regulator of this process. The broad aim of this project is to use molecular, genomic, embryological and imaging techniques to investigate fundamental open questions pertaining the origin, formation and fate of the gut endoderm in mammals.
Specific Aim 1 will investigate the dynamic cellular behaviors driving gut endoderm morphogenesis.
Specific Aim 2 will probe the mechanism(s) by which the SOX17 transcription factor drives gut endoderm cell fate specification, tissue morphogenesis and communication between embryonic definitive endoderm and extra-embryonic visceral endoderm cells as they form a congruent epithelium.
Specific Aim 3 will determine whether descendants of extra-embryonic visceral endoderm cells persist throughout embryonic development and whether they will ultimately contribute to the endodermal organs of the adult. A rigorous understanding of the normal gut endoderm, encompassing its origin, formation and fate, will underpin logical efforts to direct the differentiation of cells into endoderm identities, generate bona fide endodermal organoids for development and disease modeling and screening, understand disease progression and design new therapeutic strategies for these vital organ systems when they fail.
/ PUBLIC HEALTH RELEVANCE STATEMENT The major cell types of many of our internal organs, including the thyroid, thymus, lung, stomach, liver, pancreas, intestine and bladder arise from a common embryonic tissue called the gut endoderm. A rigorous understanding of how the gut endoderm normally forms, including knowledge of the origin of its resident cell populations, how these cell types are generated during embryonic development, and how they are diversified to form individual organs with distinct characteristics, will underpin logical efforts to understand the manifestation and progression of diseases in these vital internal organs, tissue regeneration potential and repair, as well as the progression and design new therapeutic strategies. The broad aim of this project is to use a combination of state-of-the-art embryological, genetic, single-cell genomic and imaging techniques to determine the origin and fate of the embryonic gut endoderm, and to investigate the cell behaviors driving its formation in the embryo.