Dependence for TEAD transcription factors in intestinal development and polyposis

摘要 在脊椎动物发育过程中，内脏内胚层招募相邻的中胚层形成原始的肠管， 随后产生胃肠道(GI)。胃肠道内的器官发生和组织内稳态 需要内胚层上皮和相邻间充质之间持续的串扰。杰出的 该领域的研究阐明了控制肠上皮自我更新的关键调控机制 和再生。然而，人们对胃肠道间充质干细胞的生物学知之甚少。在肠道发育过程中， 内脏中胚层在肠道发育过程中发生了显著的变化；它有别于薄的 将祖细胞层转化为由平滑肌细胞、成纤维细胞和内皮细胞组成的复杂组织 细胞。更重要的是，间充质/间质功能障碍也与许多消化系统疾病密切相关。 疾病和癌症。因此，了解间充质生长的遗传和分子基础 而分化可能会导致未来设计出新的有效的胃肠道疾病治疗策略。我们的 最近的工作发现了GI间充质中以前未被认可的河马/YAP信号的要求 在胚胎发育过程中协调生长和构图。Tead家族转录因子是 被认为是河马/YAP信号输出的主要中介；然而，TEAD的生理作用 哺乳动物发育中的蛋白质仍然没有得到很好的描述。在此应用程序中，我们将使用组合 严谨的小鼠遗传学和化学生物学方法来破译这些角色和潜在的机制 TEAD在肠道发育和动态平衡中的调节。在具体目标1中，我们将定义机制 在肠道间充质中潜在的AP1-YAP/TEAD合作。在具体目标2中，我们将探索YAP/TAZ- 独立TEAD在肠道发育中的作用。在具体目标3中，我们将使用化学生物学方法来 确定棕榈酰化在错构瘤性息肉病中的功能意义。成功者 完成本申请中的拟议研究将为我们的理解提供重大进展 了解胃肠道发育、动态平衡和发病机制的基本机制。

SUMMARY 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.