Jason Mills, MD, PhD

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.

Editorial Responsibilities

2010 – Present	Associate Editor	Physiological Genomics
2010 – 2010	Guest Associate Editor	Gastroenterology
2009 – Present	Editorial Board Member	Gastroenterology
2008 – Present	Editorial Board Member	Digestive Diseases and Sciences
2008 – Present	Editorial Board Member	American Journal of Physiology: Gastrointestinal and Liver Physiology

Service to the Department

2009 – 2010	Director Research Track Residency Recruitment
2004 – Present	Attending Pathologist, Autopsy Service

Service to the University

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

DBBS Graduate Program Affiliation

• Developmental Biology
• Molecular Cell Biology
• Immunology Program
• Molecular Genetics & Genomics