Biology and Biomedical Sciences: Developmental, Regenerative and Stem Cell Biology
Date of Award
Doctor of Philosophy (PhD)
Chair and Committee
Craig A Micchelli
A fundamental question in biology is how cellular systems sense and respond to their environment. The environment is a changing parameter, and cellular life has evolved a multitude of interesting and adaptive ways to sense and respond to external changes. The GI tract is a particularly interesting tissue in which to examine this question. One of few barrier epithelia, the intestine is exposed to both the unique environment of the lumen and the internal environment of the organism. Cells of the intestine simultaneously function as barrier, digestive organ, and sensory organ. Additionally, in many metazoan animals these functions occur in the context of active stem cell based turnover. Although substantial progress has been made in the identification of the genetic and molecular pathways that regulate these different processes, the manner in which function is responsive to changes in the environment remains incompletely understood.
In this dissertation, we used the adult Drosophila midgut as a model system to investigate two aspects of intestinal homeostasis in response to environmental change. Chapters 2 and 3 address the regulation of intestinal stem cell based renewal as a coordinated and phenotypically plastic system. In Drosophila, as in mammals, the adult intestinal epithelium is maintained by self-renewing and multipotent stem cells. A critical aspect of the success of adult stem cell renewing systems is the balance and regulation of proliferation, self-renewal, and differentiation. In Chapter 2 we demonstrate the requirement for JAK/STAT signal transduction in the ISC lineage for multilineage differentiation. Work concurrent with ours was important in demonstrating the induction of JAK/STAT pathway ligands in response to intestinal stressors including enteric pathogens. Thus, JAK/STAT is an important pathway that coordinates proliferation and mulitlineage differentiation during epithelial renewal. In Chapter 3, we characterized the Apc loss of function phenotype in the ISC lineage. Apc is a repressor of Wnt signalling in mammals and Drosophila. Apc loss of function mutations had been shown to be a causative mutation associated with colon cancers in humans, however the intrinsic requirement of Apc in the ISC lineage itself had not been tested. We report that Apc is necessary within the lineage to repress ISC proliferation. This finding is important in establishing the groundwork for future investigation of the responsivity of hyperplastic lineages to changes in the inflammatory and nutritional environment.
Chapter 4 characterizes a novel response of the enteroendocrine system to pathogenic challenge. Enteroendocrine cells are professional secretory cells with the capacity to signal through various peptide hormones. These hormones regulate important aspects of local and organismal physiology. We discovered and characterized a prosecretory response of the mature enteroendocrine population to the pathogenic bacteria Pseudomonas entomophila. Specifically, the prosecretory bHLH transcription factor Dimmed is induced in a manner that is transient, sensitive to low doses and required for expression of the important peptide processing enzyme phm.
Taken together, these studies provide mechanistic insight into our understanding of renewal and enteroendocrine function as regulated and responsive processes. It remains an interesting question the extent to which these pathways are mechanistically integrated or operate independently from one another.
Beebe, Katherine, "Dynamic Responses at the Barrier Epithelium" (2014). All Theses and Dissertations (ETDs). 1287.