The findings are reported in the September 19 online issue of Nature Genetics (click here to view a PDF copy of the paper) and in the October 2004 print edition where a commentary on Dr. Li’s paper appears in the “News and Views” section (click here to view a PDF copy).

     Intestinal stem cells are a subset of cells located at the base of the intestinal crypt that are capable of self-renewal and production of all types of cells lining the cavity of the intestine. Normally these cells proliferate and differentiate so that appropriate numbers of functional epithelial cells maintain the integrity of the intestinal lining. However, these stem cells sometimes produce too many progeny, and intestinal polyps form. Understanding the factors that govern the size of the intestinal stem cell population should shed light on the molecular pathology of human genetic diseases such as juvenile polyposis syndrome, juvenile intestinal polyposis, and Cowden’s disease. The development of numerous polyps is a common feature of these diseases, suggesting an association between mutated signaling pathways and regulation of stem cell proliferation.

     Dr. Li’s team demonstrated that BMP signaling suppresses Wnt signaling to ensure a balanced control of stem cell self-renewal in the intestine. BMP proteins and their receptors were first characterized as having effects on bone development but are now known to exert numerous effects in a variety of different systems. Wnt proteins are highly conserved signaling molecules that regulate cell fate determination and morphogenesis in embryos as well as stem cell self-renewal in adults. Using mutations that inactivate BMP signaling in mice, Dr. Li and his collaborators disturbed the homeostasis of intestinal epithelial regeneration, expanded the stem cell population, and caused the formation of intestinal polyps that created a condition resembling human juvenile polyposis syndrome.

     “These findings are exciting,” said Robb Krumlauf, Ph.D., Scientific Director of the Stowers Institute, “because they significantly advance our understanding of key signaling pathways that govern the regulation of cellular decisions during differentiation and provide a means of building a picture of the genetic pathways that control organ development.”

     “Jim and Virginia Stowers believe that highest quality basic research holds the key to understanding human disease,” said William Neaves, Ph.D., President and CEO of the Stowers Institute. “The work published by Dr. Li and his colleagues in Nature Genetics reinforces the Stowers’ commitment to understanding how genes and proteins control fundamental processes in living cells. His findings open new opportunities for research on stem cells that could eventually lead to more effective therapies.”

     Joining Stowers Institute scientists in conducting the study were researchers from Harvard Medical School, Kansas University Medical Center, the Institute for Systemsbiology – Seattle, and the National Institutes of Health. In addition to his primary appointment at the Stowers Institute, Dr. Li holds a faculty appointment at the University of Kansas School of Medicine.

     Situated on a 10-acre campus in the heart of Kansas City, Missouri, the Stowers Institute for Medical Research conducts research on the fundamental processes of cellular life. Through basic research of the highest quality, the Stowers Institute seeks insights that will lead to more effective ways of preventing and curing disease. The Institute was founded in 1994 by Jim and Virginia Stowers, two cancer survivors who have dedicated their fortune to supporting the basic research that will provide long-term solutions to gene-based diseases.