This proposal aims to identify how serotonin cells become specialized to produce this hormone and to examine their potential to form neuroendocrine tumors in mice. Understanding how potentially normal cells give rise to carcinoids will be important for identifying new therapeutic targets for treating these tumors. Dr. Leiter developed methods to isolate relatively pure serotonin cells from the stomach and the small intestine and analyzed all the genes expressed by RNA Sequencing.
In addition to serotonin-producing endocrine cells, Dr. Leiter’s group identified a new population of serotonin cells. which appeared to be mast cells. Mast cells are a bone marrow cell involved in immune regulation. Mast cells migrate to and reside in the intestine and produce serotonin.
In addition to serotonin cells, Dr. Leiter extended the original project to study histamine producing cells in the stomach which some investigators propose is a mast cell. This population was chosen because these cells are believed to be the source for many stomach carcinoids. The gene expression pattern of these cells clearly suggested that they were endocrine cells, not bone marrow-derived mast cells.
Ray SK, Li HJ, Metzger E, Schüle R, Leiter AB. CtBP and associated LSD1 are required for transcriptional activation by NeuroD1 in gastrointestinal endocrine cells. Mol Cell Biol. 2014 Jun; 34(12): 2308–2317. doi: 10.1128/MCB.0160013
Li HJ, Johnston B, Aiello D, Caffrey DR, Giel-Moloney M, Rindi G, Leiter AB. Distinct cellular origins for serotonin-expressing and enterochromaffin-like cells in the gastric corpus. Gastroenterology. 2014 Mar;146(3):754-764.e3. doi: 10.1053/j.gastro.2013.11.048. Epub 2013 Dec 4.
Li HJ, Kapoor A, Giel-Moloney M, Rindi G, Leiter AB. Notch signaling differentially regulates the cell fate of early endocrine precursor cells and their maturing descendants in the mouse pancreas and intestine. Dev Biol. 2012 Nov 15;371(2):156-69. doi: 10.1016/j.ydbio.2012.08.023. Epub 2012 Sep 1.
Li HJ, Ray SK, Singh NK, Johnston B, Leiter AB. Basic helix loop helix transcription factors and enteroendocrine cell differentiation. Diabetes Obes Metab. 2011 Oct; 13(0 1): 5–12. doi: 10.1111/j.14631326.2011.01438.
Wang Y, Giel-Moloney M, Rindi G, Leiter AB. Enteroendocrine precursors differentiate independently of Wnt and form serotonin expressing adenomas in response to active β-catenin. Proc Natl Acad Sci U S A. 2007 Jul 3; 104(27): 11328–11333. Published online 2007 Jun 25. doi: 10.1073/pnas.0702665104.