Mechanisms of Physiological Organ Shrinkage

点击翻译按钮获取中文摘要

PROJECT SUMMARY Many adult organs--for instance, intestine, mammary gland, skeletal muscle, skin—respond to reduced levels of functional demand by shrinking their physical size. In these organs, cells are lost faster than they are made, leading to a reduction in total cell number. The intestine is a broadly conserved exemplar of demand- driven organ shrinkage. In wild animals, cyclic periods of starvation cause intestinal size to shrink by 60-75%. Humans also undergo healthy intestinal shrinkage, but excessive or dysregulated cell loss can quickly become pathological, as seen in enteropathies like celiac sprue, endotoxemia, and giardiasis. Yet—unlike the mechanisms that balance cell division/loss during everyday turnover—the mechanisms that tune cell imbalance for physiological shrinkage are virtually unknown. The roadblock to mechanistic investigation of intestinal shrinkage has been the lack of a tractable laboratory model, which must allow cells (and their dynamic behaviors) to be monitored across time and must possess cell-specific markers and other tools to facilitate mechanistic studies. Historically, studies used rodents, but modern research protocols cannot replicate natural famine/feast cycles. My lab has developed a new invertebrate model of intestinal shrinkage that is both tractable and genetically manipulable: the Drosophila adult midgut, akin to the vertebrate small intestine. We demonstrate that intestinal shrinkage is conserved in Drosophila, and we document that its underlying basis is the massive squeezing-out of now-superfluous enterocytes through active extrusion. Here, we investigate intestinal shrinkage from both sides of the equation for net cellular balance: mature cell loss (Aim 1) and stem cell capacity (Aim 2). Our studies leverage the midgut’s superlative toolkit of cell- specific genetic reporters and our own pioneering innovations for real-time and longitudinal imaging of functioning midguts inside live animals. In Aim 1, we ask how the gut senses loss of ingested food— mechanical compression, lack of nutrients, or both. We test if two known regulators of extrusion, the transcriptional co-activator YAP/Yorkie and intercellular Ca2+ waves, function during shrinking to increase extrusions. Third, we probe whether a shrinking gut regulates cell extrusions at the organ scale or at the level of individual cells. In Aim 2, we seek the mechanisms that cause a 75% culling of the stem cell pool during shrinkage—even as stem cell mitoses paradoxically increase. We will test if stem cells initiate non-self- renewing divisions, adopt terminal fates directly, and/or activate apoptosis. The fly gut’s digestive physiology, stem cell lineages, and molecular regulation are similar to humans. Hence by elucidating the cell-to-organ scale mechanisms that operate at this frontier of tissue biology, this project may yield leads for therapies to treat cellular imbalances in human disease.