The digestive tract (stomach and intestine) is an ideal organ to investigate processes of fundamental biomedical interest:
- Embryonic development and organogenesis
- Self-renewal of adult tissues
- Properties of progenitor and stem cells
- Tissue-specific gene regulation
- Inductive tissue interactions in development and homeostasis
- The intersection of signaling and transcriptional control
This is because the digestive tract develops early in embryos, with a large mass that reflects inductive interactions between the definitive endoderm and splanchnic mesoderm. In young and adult animals, the organ remains large and readily accessible, with an abundant supply of continually self-renewing stem and progenitor cells. The progeny of the latter cells replace the full mucosal lining every few days, and the well-defined microscopic anatomy allows this process to be monitored in detail.
Our laboratory takes advantage of these features to study molecular mechanisms of gut development and tissue diferentiation, particularly the transcriptional and chromatin basis for cell diversity in response to local signals. Our research typically combines mouse genetics with molecular, developmental, cell, and computational biology.
The intestinal epithelium is also the origin of colorectal cancer, the second leading cause of cancer death in the West (50,000 deaths annually in the US alone). A refined appreciation of the developmental and stem-cell underpinnings of the normal epithelium will serve as a foundation for future rational preventive and treatment strategies.
Background: The digestive tract develops as a result of interactions between cells derived from the embryonic endodermal and mesodermal germ layers. The endoderm gives rise to the digestive epithelia, while adjacent mesoderm produces mesenchyme and smooth muscle. To understand the cellular and molecular basis of gut development, we study (1) differentiation of primitive endoderm into gut-specific epithelia, (2) patterning of the foregut, midgut and hindgut, and (3) intercellular communication within and between the endodermal and mesenchymal compartments.
After birth, the stomach and intestine develop distinct epithelial compartments that house long-lived stem and short-lived progenitor cells. These cells have an enormous capacity for self-renewal and differentiate briskly into the resident epithelial cell types: absorptive and secretory cells in the intestine, and various types of secretory cells in the stomach. These lineages are controlled by a few select transcription factors, which we investigate in considerable detail. These transcription factors respond to local signals (such as Wnt, Hedgehog, Notch and Bone Morphogenetic Protein, BMP4) and the native chromatin environment to regulate expression of tissue-specific genes. The overarching goal of the laboratory is to understand how these processes influence and control each other.