John B. Lowe, M.D.
Professor,
Department of Pathology
Investigator, Howard Hughes Medical Institute

johnlowe@umich.edu

Research in the Lowe Laboratory has focused on understanding the structures and regulation of the genes that determine mammalian cell surface glycan structure, and on the function of such molecules. A major focus of the lab is to explore the functions of such molecules through the creation and analysis of mice with targeted deletions of specific genes required for the elaboration of specific cell surface glycan moieties. This work has most recently involved the discovery of several genes and a corresponding set of glycans that control lymphocyte homing, and that are required for the recruitment of neutrophils, monocytes, T lymphocytes, and other leukocytes in acute and chronic inflammation. This work has recently expanded to the study of how subsets of these glycans control the myelopoietic program in the marrow. This work has also turned recently to explore the role of glycan-dependent modulation of signal transduction events in the immune system that are mediated by the Notch family of transmembrane signal transduction receptors and their cognate ligands. Mice with inducible regulation of such glycans are in use to define immune cell fate determination mediated by Notch and its ligands.

The laboratory is also studying the molecules and mechanisms used by dendritic cells to "mature", and to migrate through tissues to secondary lymphoid organs. Langerhans cells, a type of dendritic cell that populates the skin, is serving as a model for study of this process. Molecular cloning approaches have been developed in and utilized by the lab to identify a set of genes whose expression is dynamically regulated during the process whereby Langerhans cells that reside in the epidermis are (1) induced to disengage from their epidermal moorings, (2) migrate across the basement membrane separating the epidermis and dermis, (3) locate and enter terminal lymphatics in the dermis, (4) migrate through these lymphatics to a regional lymph node and (5) locate T cell zone in the node, all the while undergoing maturation into potent antigen presenting cells. Transgenic and gene deletion experiments in mice, and retroviral transduction experiments in vitro are underway in the laboratory to understand the contributions to these complex and important dendricitc cell migration and maturation events made by several of these dynamically-regulated genes.

Representative Publications

Lowe JB. Glycosylation, Immunity, and Autoimmunity. Cell 104: 809-812, 2001.


Yeh J-C, Hiraoka N, Petryniak B, Nakayama J, Ellies LG, Rabuka D, Hindsgaul O, Marth JD, Lowe JB, and Fukuda M. Novel sulfated lymphocyte homing receptors and their control by a new core 1 extension bet1,3-N-acetylglucosaminyltransferase. Cell 105:957-969, 2001.

Homeister JH, Thall A, Petryniak B, Maly P, Rogers CE, Smith PL, Kelly RJ, Gersten KM, Misra A, Cheng G, Askari S, Smithson G, Marks RM, Hindsgaul O, von Adrian UH, and Lowe JB. The alpha(1,3)fucosyltransferases Fuc-TIV and Fuc-TVII exert collaborate control over selectin-dependent leukocyte recruitment and lymphocyte homing. Immunity 15: 115-126, 2001.

Smithson G, Rogers CE, Smith PL, Scheidegger EP, Petryniak B, Myers JT, Kim DSL, Homeister JW, and Lowe JB. Fuc-TVII is required for Th1 and Tc1 lymphocyte selectin ligand expression and recruitment in inflammation, and together with Fuc-TIV regulates naïve T cell trafficking to lymph nodes. J Exp Med. 194: 601-614, 2001.

Lowe JB. Glycosylation in the Control of Selectin Counter-receptor Structure and Function. Immunol Rev 186:19-36, 2002.

Smith PL, Myers JT, Rogers CM, Zhou L, Petryniak B, Becker DE, Homeister JW, and Lowe JB. Conditional control of selectin ligand expression and global fucosylation events in mice with a targeted mutation at the FX locus. J Cell Biol 158:801-815, 2002.

Lowe JB and Marth JD. Genetic approaches to glycan function in mammals. Annu Rev Biochem 72:643-691, 2003.