During vertebrate development, the visceral endoderm recruits adjacent mesoderm to form a primitive gut tube, which later gives rise to the gastrointestinal (GI) tract. Organogenesis and tissue homeostasis within the GI tract require continuous crosstalk between endodermal epithelium and the adjacent mesenchyme. Outstanding studies in the field have elucidated the critical regulatory mechanisms controlling intestinal epithelial self-renewal and regeneration. However, little is known about the biology of GI mesenchyme. During gut development, the visceral mesoderm undertakes remarkable transformation during gut development; it differentiates from a thin layer of progenitor cells into a complex tissue comprised of smooth muscle cells, fibroblasts, and endothelial cells. More importantly, mesenchymal/stromal dysfunction is also closely associated with many digestive diseases and cancers. Thus, understanding the genetic and molecular bases underlying mesenchymal growth and differentiation may lead to future design of novel and effective therapeutic strategies for GI diseases. Our recent work identified a previously unappreciated requirement of Hippo/YAP signaling in GI mesenchyme to coordinate growth and patterning during embryonic development. The TEAD family transcription factors are considered as the major mediator of Hippo/YAP signaling output; however, the physiological roles of TEAD proteins in mammalian development remain poorly characterized. In this application, we will use a combination of rigorous mouse genetics and chemical biology approaches to decipher the roles and underlying mechanism of TEAD regulation in gut development and homeostasis.
In Specific Aim 1, we will define the mechanism underlying AP1-YAP/TEAD cooperation in gut mesenchyme.
In Specific Aim 2, we will explore the YAP/TAZ- independent TEAD function in gut development.
In Specific Aim 3, we will use a chemical biology approach to determine the functional significance of TEAD palmitoylation in hamartomatous polyposis. The successful completion of the proposed studies in this application will provide significant progress towards our understanding of the fundamental mechanisms underlying GI development, homeostasis and pathogenesis.
In this project the investigators seek to understand novel mechanisms of embryonic development and postnatal growth control in the gastrointestinal tract. Our study is focused on gastrointestinal mesenchyme, a fundamentally important tissue layer within the gastrointestinal tract that is often understudied. The proposed studies on regulation of the critical YAP/TEAD signaling in gut mesenchyme are essential to gain mechanistic insights into and develop new therapeutic strategies for GI diseases.