Jason Mills, M.D., Ph.D.


Mills Lab

Jason Mills, M.D., Ph.D.

Associate Professor of Medicine, Developmental Biology and of Pathology & Immunology

Bio:

Jason Mills joined the Division of Gastroenterology, Department of Medicine in January, 2011. He also holds appointments in Pathology & Immunology as well as Developmental Biology. Dr. Mills graduated summa cum laude from Washington University as an undergraduate, where he was the Moog scholar in humanities and sciences, majoring in Russian and biology. He received his MD and PhD from the University of Pennsylvania, where he studied the role of the cytoskeleton in apoptosis. He came back to Washington University for his residency in Anatomical Pathology and a postdoctoral fellowship in Jeff Gordon’s lab, where he studied genomics of gastric epithelial differentiation. He has had his own lab at Washington University since 2004, studying epithelial differentiation in the GI tract during development, injury/inflammation, and carcinogenesis. Dr. Mills is the recipient of an American Cancer Society Research Scholar Award, as well as the 2010 Funderburg Award in Gastric Biology Related to Cancer and the 2010 Washington University Faculty Mentor Award. He is an Associate Editor for the journal Physiological Genomics, and he serves on the Editorial Board of Gastroenterology, Digestive Diseases and Sciences, and The American Journal of Physiology GI Liver. Dr. Mills has over 50 articles and books, which have been cited over 1500 times with an h index of 20.

Research Interests:

My lab is using a multipronged approach to understand the cellular and molecular details of adult stem cell biology in the mouse and human GI tract. We are interested both in normal developmental pathways from the multipotent stem cell and in uncovering the aberrations that occur when those pathways go awry (e.g., in stomach cancer). In particular, we have focused recently on how mucus-secreting neck cells arise from a multipotent gastric epithelial stem cell and then undergo a dramatic differentiation into digestive-enzyme-secreting zymogenic (chief) cells. In one set of experiments, we combine mouse genetics, human histopathology and bioinformatic promoter/expression analyses, as well as in vitro mechanistic studies to identify the first gene, the bHLH transcription factor MIST1 (BHLHA15), required for normal maturation of zymogenic cells. We have shown that differentiation of zymogenic cells occurs because another transcription factor, XBP1, controls expression of genes that induce massive deposition of rough endoplasmic reticulum (rER) and also upregulates MIST1, which, in turn, regulates genes that form the cell's apical storehouse of large secretory granules. In the absence of XBP1, neither rER nor vesicles form normally, and zymogenic cells show metaplastic differentiation: namely, they are unable to stop expression of neck (i.e., progenitor) genes.

Our research highlights how remarkably plastic zymogenic cells are. Normally, they are postmitotic and long-lived. In the face of metaplasia-inducing injury (e.g., experimentally induced loss of XBP1 or, in certain patients, infection with the pathogen Helicobacter pylori), they can re-enter the cell cycle and then regain stem cell properties, fueling differentiation of other gastric lineages. In other words, they are an example of a naturally occurring, induced multipotent stem cell. We are dissecting the genes involved in these transitions that may be at the root of gastric cancer.

In a related project that dovetails developmental biology and cell biology, we are interested in how a relatively limited number of developmentally regulated transcription factors, like XBP1 and MIST1, coordinate assembly of the specialized cellular machinery required by diverse terminally differentiated cells. For example, gastric zymogenic cells and bone marrow plasma cells arise via entirely different cellular lineages and don't secrete the same substances, yet they both require the transcription factor sequence of XBP1->MIST1 to reach structural maturity. The MIST1 ortholog in flies, DIMM, also regulates cell size and secretory granule formation, suggesting the existence of well conserved transcriptional modules available to certain cells to become secretory specialists. To understand how this works throughout evolution, we are interested in characterizing MIST1 target genes and, in collaboration with the lab of Dr. Paul Taghert also here at Wash U, determining how molecular mechanisms of MIST1 and DIMM intersect.

Key Publications:

  1. Mills JC, Shivdasani RA. Gastric epithelial stem cells. Gastroenterology. 2011; 140:412-424.
  2. Capoccia BJ, Lennerz JK, Bredemeyer AJ, Klco JM, Frater JL, Mills JC. The transcription factor MIST1 in terminal differentiation of mouse and human plasma cells. Physiol Genomics. 2010
  3. Huh WJ, Esen E, Geahlen JH, Bredemeyer AJ, Lee AH, Shi G, Konieczny SF, Glimcher LH, Mills JC. XBP1 controls maturation of gastric zymogenic cells by induction of MIST1 and expansion of the rough endoplasmic reticulum. Gastroenterology. 2010;139:2038-2049.
  4. Lennerz JK, Kim SH, Oates EL, Huh WJ, Doherty JM, Tian X, Bredemeyer AJ, Goldenring JR, Lauwers GY, Shin YK, Mills JC. The transcription factor MIST1 is a novel human gastric chief cell marker whose expression is lost in metaplasia, dysplasia, and carcinoma. Am J Pathol. 2010; 177:1514-1533.
  5. Tian X, Jin RU, Bredemeyer AJ, Oates EJ, Błazewska KM, McKenna CE, Mills JC. RAB26 and RAB3D are direct transcriptional targets of MIST1 that regulate exocrine granule maturation. Mol Cell Biol. 2010; 30:1269-1284.
  6. Bredemeyer AJ, Geahlen JH, Weis VG, Huh WJ, Zinselmeyer BH, Srivatsan S, Miller MJ, Shaw AS, Mills JC. The gastric epithelial progenitor cell niche and differentiation of the zymogenic (chief) cell lineage. Dev Biol. 2009; 325:211-224.
  7. Ramsey VG, Doherty JM, Chen CC, Stappenbeck TS, Konieczny SF, Mills JC. The maturation of mucus-secreting gastric epithelial progenitors into digestive-enzyme secreting zymogenic cells requires Mist1. Development. 2007; 134:211-222.

 

Link to Medline for selected publications

Division of Gastroenterology
Department of Medicine
Washington University School of Medicine