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Research > Faculty Alphabetical > Jason Mills, MD, PhD

Associate Professor, Medicine
Associate Professor, Pathology and Immunology
Associate Professsor, Developmental Biology
Room 1030, CSRB - North Tower Annex
Office: (314) 362-4213
Lab: (314) 362-4258
E-mail: jmills@wustl.edu
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Research

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.

Editorial Responsibilities

2010 - PresentAssociate EditorPhysiological Genomics
2010 - 2010Guest Associate EditorGastroenterology
2009 - PresentEditorial Board MemberGastroenterology
2008 - PresentEditorial Board MemberDigestive Diseases and Sciences
2008 - PresentEditorial Board MemberAmerican Journal of Physiology: Gastrointestinal and Liver Physiology

Service to the Department

2009 - 2010Director Research Track Residency Recruitment
2004 - PresentAttending Pathologist, Autopsy Service

Service to the University

2011 - PresentDiscussion Leader, Molecular Cell Biology 5068
2011 - PresentDirector DDRCC Pilot & Feasibility Award Program
2011 - PresentCo-Director Morphology Core, DDRCC
2009 - PresentChair, DBBS Admissions Committee B
2006 - 2006Lecturer, Contemporary Molecular Immunology 530
2005 - PresentLecturer & Lab discussion leader, 2nd year Medical School Pathology Course
2005 - 2005Section leader, Biology 5011, Ethics & Research Science
2005 - PresentMember, Developmental Biology Graduate Group Steering Committee
2005 - 2010Discussion Leader, Medical School Immunology Case Sessions
2005 - 2008Discussion Leader, Molecular Cell Biology 5068
2005 - PresentLecturer, Advanced Genetics, Bio 5491
2005 - PresentMember, DBBS Admissions Committee
2004 - 2006Lecturer, Advanced Topics in Immunology 5272

DBBS Graduate Program Affiliation

Developmental Biology
Molecular Cell Biology
Immunology Program
Molecular Genetics & Genomics

Diagnostic Expertise

Attend on autopsy service

Clinical Interest

Anatomic and Molecular Pathology - Autopsy Pathology

Selected Publications

Huh WJ, Khurana SS, Geahlen JH, Kohli K, Waller RA, Mills JC. Tamoxifen induces rapid, reversible atrophy and metaplasia in mouse stomach. Gastroenterology;142:21-24.e7, 2012 Abstract

Mills JC, Taghert PH. Scaling Factors: transcription factors regulating subcellular domains. Bioessays;34:10-16, 2012 Abstract

Goldenring JR, Nam KT, Mills JC. The origin of pre-neoplastic metaplasia in the stomach: Chief cells emerge from the Mist. Exp Cell Res;317:2759-2764, 2011 Abstract

Lim JW, Hummert P, Mills JC, Kroll KL. Geminin cooperates with Polycomb to restrain multi-lineage commitment in the early embryo. Development ;138:33-44, 2011 Abstract

Cappocia BJ, Lennerz JKM, Bredemeyer AJ, Klco JM, Frater JL, Mills JC. The transcription factor MIST1 in terminal differentiation of mouse and human plasma cells. Physiol Genomics;43:174-186, 2011 Abstract

Goldenring JR, Nam KT, Wang TC, Mills JC, Wright NA. Spasmolytic polypeptide-expressing metaplasia and intestinal metaplasia: Time for reevaluation of metaplasias and the origins of gastric cancer. Gastroenterology;140:412-424, 2010 Abstract

Mills JC, Shivdasani RA. Gastric epithelial stem cells. Gastroenterology;140:412-424, 2010 Abstract

Tian X, Jin RU, Bredemeyer AJ, Oates EJ, Blazewska KM, McKenna CE, Mills JC. RAB26 and RAB3D are direct transcriptional targets of MIST1 that regulate exocrine granule maturation. Mol Cell Biol;;30(5):1269-1284, 2010 Abstract

Huh WJ, Mysorekar IU, Mills JC. Inducible expression of Cre recombinase in adult mice causes gastric epithelial atrophy, metaplasia and regenerative changes in the absence of "floxed" alleles.. Am J Physiol Gastrointest Liver Physiol; 299:G368-380, 2010 Abstract

Lennerz JKM, Kim S-K, Oates EJ, Tian X, Bredemeyer AJ, Goldenring JR, Lauwers GY, Shin Y-K, Mills JC. The transcription factor MIST1 is a novel human gastric chief cell marker whose expression is lost in metaplasia, dysplasia and carcinoma. Amer J Pathol;177:1514-1533, 2010 Abstract

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;139:2038-2049, 2010 Abstract

Nam KT, Lee HJ, Sousa JF, O’Neal RL, Finke PE, Romero-Gallo J, Shi G, Mills JC, Peek RM Jr, Konieczny SF, Goldenring JR. Mature chief cells are cryptic progenitors for metaplasia in the stomach.. Gastroenterology;139:2028-2037, 2010 Abstract

Capoccia BJ, Huh WJ, Mills JC.. How form follows functional genomics: Gene expression profiling gastric epithelial cells with a particular discourse on the parietal cell. Physiological Genomics;37:67-78, 2009 Abstract

Cella M, Fuchs A, Vermi W, Facchetti F, Otero K, Lennerz JK, Doherty JM, Mills JC, Colonna M. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature; 457:722-725, 2009 Abstract

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; 328:456-471, 2009 Abstract

Mysorekar IU, Isaacson-Schmid M, Walker JN, Mills JC, Hultgren, SJ. Bone Morphogenetic Protein 4 Signaling Regulates Epithelial Renewal in the Urinary Tract in Response to Uropathogenic Infection. Cell Host and Microbe;5:463-475, 2009 Abstract

Calderon B, Suri A, Pan XO, Mills JC, Unanue ER. IFN-gamma-dependent regulatory circuits in immune inflammation highlighted in diabetes. J. Immunol.;181:6964-74, 2008 Abstract

Doherty JM, Geske MJ, Stappenbeck TS, Mills JC. Diverse adult stem cells share specific higher-order patterns of gene expression. Stem Cells; 26: 2124-30, 2008 Abstract

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.;134:211-222, 2007 Abstract

Lugus JJ, Chung YS, Mills JC, Kim SI, Grass JA, Kyba M, Doherty JM, Bresnick EH, Choi K. GATA2 functions at multiple steps in hemangioblast development and differentiation. Development;134(2):393-405, 2007 Abstract

Doherty JM, Carmichael LK, Mills JC. GOurmet: A tool for quantitative comparison and visualization of gene expression profiles based on gene ontology (GO) distributions. BMC Bioinformatics 7:151, 2006 Abstract

Giannakis M, Stappenbeck TS, *Mills JC (co first author), Leip DG, Lovett M, Clifton SW, Ippolito JE. Molecular properties of adult mouse gastric and intestinal epithelial progenitors in their niches. J Biol Chem 281:11292-11309, 2006 Abstract

Huh WJ, Pan XO, Mysorekar IU, Mills JC. Location, allocation, relocation: isolating adult tissue stem cells in three dimensions. Curr Opin Biotechnol;17:511-517, 2006 Abstract

Pull SL, Doherty JM, Mills JC, Gordon JI, Stappenbeck TS. Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. Proc Natl Acad Sci USA 102:99-104, 2005 Abstract

Syder AJ, Karam SM, Mills JC, Ippolito JE, Ansari HR, Farook V, Gordon JI. A transgenic mouse model of metastatic carcinoma involving transdifferentiation of a gastric epithelial lineage progenitor to a neuroendocrine phenotype. Proc Natl Acad Sci USA 101:4471-4476, 2004 Abstract

Mills JC, Andersson N, Stappenbeck TS, Chen CC, Gordon JI. Molecular characterization of mouse gastric zymogenic cells. J Biol Chem 278: 46138-46145, 2003 Abstract

Mills JC, Andersson N, Hong CV, Stappenbeck T, Gordon JI. Molecular characterization of mouse gastric epithelial progenitor cells. Proc Natl Acad Sci USA 99:14819-14824 [This article featured in a Selected Summary by Erwin CR, Jarboe M, Warner BW in Gastroenterology 125:266-267 w, 2002 Abstract

Mills JC, Gordon JI. A new approach for filtering noise from high-density oligonucleotide microarray datasets. Nucleic Acids Res 29:E72, 2001 Abstract

Mills JC, Roth KA, Cagan RL, Gordon JI. DNA microarrays and beyond: completing the journey from tissue to cell. Nat Cell Biol 3:E175-178, 2001 Abstract

Mills JC, Syder AJ, Hong CV, Guruge JL, Raaii F, Gordon JI. A molecular profile of the mouse gastric parietal cell with and without exposure to Helicobacter pylori. Proc Natl Acad Sci USA 98:13687-13692, 2001 Abstract

Mills JC, Gordon JI. The intestinal stem cell niche: There grows the neighborhood. Proc Natl Acad Sci USA 98:12334-12336, 2001 Abstract

Mills JC, Stone NL, Pittman RN. Extranuclear apoptosis: The role of the cytoplasm in the execution phase. J Cell Biol 146:703-708, 1999 Abstract

Liu JY, Seno H, Miletic AV, Mills JC, Swat W, Stappenbeck TS. Vav proteins are necessary for correct differentiation of mouse cecal and colonic enterocytes. J Cell Sci, 122:324-33 Abstract