Solving regulatory circuits controlling gut organogenesis An important question in developmental biology is how the spatial organization of body parts, organs, and cell types within the animal body plan is acquired with such accuracy and reproducibility during animal development according to genomic instructions. Gene regulatory networks (GRNs) encode these instructions and thereby provide the mechanisms for spatial organization of the body plan. GRNs control the expression of transcriptional regulators that in turn regulate the expression of cell-fate specific genes. Due to the challenges associated with experimentally analyzing GRNs in developing animals, there are so far only few developmental processes understood at the GRN level. In this project we are beginning to analyze the GRN underlying organogenesis of the gut, a developmental process that is broadly shared among animals. In order to access the developmental mechanisms underlying gut development, we will use a relatively simple deuterostome animal, the sea urchin, which facilitates system level analyses even of complicated processes such as organogenesis that might not be easily addressed in vertebrates. The sea urchin larval gut forms within 72h of fertilization and consists of multiple morphologically distinct compartments including foregut, midgut, hindgut, sphincters, mouth and anus. We recently acquired spatial expression data for over 270 regulatory genes encoding transcription factors, showing that the different compartments of the gut are distinguished at the molecular level by expression of unique combinations of transcription factors. These compartment-specific transcription factor modules are expressed prior to the appearance of morphological structure and are usually expressed over long periods of time throughout development. We will complete this analysis to identify transcription factor combinations expressed in individual endodermal cell fates within these compartments. The goal of this project is to identify the mechanisms leading to the distinct specification of foregut, midgut, hindgut, and sphincters during gut development. We will thus test the function of compartment-specific transcription factor modules by perturbation of each transcription factor and by analyzing its role in the regulation of other transcription factors and in the formation of the respective compartments. As insights on regulatory interactions accumulate, we will generate GRN models to visualize the topology of regulatory circuits and to test their dynamic and spatial behavior. The result of this project will reveal the regulatory mechanisms that control the distinct specification of the major compartments of the sea urchin gut, mechanisms that might in some form also contribute to the patterning of the anterior/posterior axis of the gut in other animals.
Disruption of genomic control mechanisms is the cause of numerous serious diseases, including developmental defects, physiological disorders and cancer. A thorough understanding of how these control mechanisms work is essential for identifying and treating any malfunctions. This is a basic research proposal with the objective to discover principles of such genomic control mechanisms by studying a common process, the development of the digestive system, in a relatively simple organism, the sea urchin embryo.
