Cedric Wesley, Ph.D.
Assistant Professor of Microbiology and Molecular Genetics
Research Program: Cell Signaling & Growth Control
VCC Membership Level: Full Member
Contact Information
332B Stafford Hall
95 Carrigan Avenue
University of Vermont
Burlington, VT 05405
ph: (802) 656-8024
f: (802) 656-8749
Cedric.Wesley@uvm.edu
Biography
Dr. Wesley received his Ph.D. in Population Genetics and Evolution from the State University of New York at Stony Brook, under the supervision of Dr. Walter Eanes. He pursued his postdoctoral work in developmental genetics at Rockefeller University, in the laboratory of Michael Young. He joined the UVM College of Medicine faculty in 2001.
Research Snapshot
Non-communication or mis-communication between cells that make up our organs and tissues results in cancers. Dr. Wesley studies a protein called Notch that is essential for communication between cells and implicated in numerous cancers.
Research
Dr. Wesley investigates cell surface mechanisms regulating metazoan development. Metazoan development processes are likely to have evolved from components of the mechanisms unicellular organisms used for communications with each other. These components likely operated at the interface between individual cells, i.e., the cell surface, and formed the prototypical developmental system in pioneer metazoans. Natural selection would have subsequently improved and elaborated on this prototype to produce the developmental systems observed in extant organisms. Dr. Wesley believes that a study of developmental regulatory mechanisms operating at cell surfaces will lead to a better understanding of the fundamental aspects of metazoan development such as the selection of germ cells and somatic cells, production and maintenance of stem cells, differentiation potentials in a stem cell population, the sequence of development of various tissues, reversible and irreversible differentiation, and advance from one differentiation stage to the next. Indeed, the transcription factors that ultimately determine cell types (by turning on or off appropriate genes) are all regulated by cell surface proteins. Thus, Dr. Wesley has initiated studies with the cell surface protein Notch.
Notch is continuously required for cell-cell communication during differentiation of all tissues in animals from worms to humans. These communications result in intracellular signals that activate different sets of genes or proteins in the different cell types produced at each stage of differentiation. Loss or excess Notch activity in humans results in developmental defects and diseases (including cancers of various tissues). The fruit fly Drosophila, with its powerful genetic and development technologies, is an excellent model system for understanding the functions of Notch during tissue differentiation. The typical series of Notch functions during tissue differentiation is illustrated in the process producing the larval Central Nervous system (CNS) and the epidermis (cuticle) in Drosophila embryos.
Notch is a 2703 amino acids long cell surface receptor. It generates intracellular signals in response to a ligand (produced by adjacent or nearby cells) binding its extracellular domain. The extracellular domain is mostly composed of 36 tandem Epidermal Growth Factor-like (EGF-like) repeats and the lin 12/Notch repeats (L/N rpts). The intracellular domain is composed of protein binding regions (e.g., RAM 23 and CDC repeats), a transcription activating sequence (OPA), and a protein turn-over sequence (PEST).
Dr. Wesley's studies indicate that at least three different Notch receptors (NFull, NDCterm, and NDNterm) are involved in production of the five different Notch signals. NDCterm and NDNterm appear to be derived from NFull in the course of differentiation by removal of intracellular or extracellular regions that are required for production of one type of Notch signal and not others. NDCterm lacks the OPA, PEST, and Dishevelled binding regions that are required for production of NFull signals; NDNterm lacks the Delta/Serrate binding region that is required for production of NFull and NDCterm signals.
NFull is the sole Notch receptor at the beginning of lateral inhibition and the process culminates with NDCterm being the sole receptor in CNS lineage and NDNterm being the sole receptor in the epidermis lineage. Thus, Notch could be part of the cell surface machinery that initiates the differentiation process in stem cells, enables differentiating cells to take appropriate developmental paths, restricts or maintains differentiation potential in cells, co-ordinates differentiation of different cells, and terminates the differentiation process in cells. This machinery might parallel the elaborate transcriptional machinery that regulates gene expression in the nucleus.
Research in Dr. Wesley's laboratory is directed towards understanding the production of the different Notch receptors, the signaling pathways utilized by the different Notch receptors, the genes or proteins regulated by these pathways, the genes or proteins that regulate the functions of different Notch receptors, and interactions between the different Notch receptors in the course of tissue differentiation in Drosophila. He will extend these studies into mammalian model systems.
There are four Notch homologs in mammals, Notch 1 to 4. Notch 1 and 2 functions resemble those of NFull, Notch 3 of NDCterm, and Notch 4 of a hypothetical receptor resembling NFull functions without the functions associated with Wingless/Scabrous/Fringe. Dr. Wesley's research will examine whether these different mammalian Notch receptors perform functions that are analogous to those of their counterparts in Drosophila and how these functions may be linked to some of the human developmental defects and cancers. He uses approaches and methods from the fields of genetics, development, evolution, molecular biology, cell biology, and biochemistry. He also plans to explore use of some biophysical and theoretical (computer-based) approaches. The overall aim of Dr. Wesley's research program is to understand the organization and basic operating principles of the metazoan differentiation process.
Recent Publications
Lecomte M, Wesley UV, Mok LP, Shepherd A, Wesley C. Evidence for the Involvement of Dominant-Negative Notch Molecules in the Normal Course of Drosophila Development. Dev Dyn. 2006 Feb;235(2):411-26.
Bardot B, Mok LP, Thayer T, Ahimou F, Wesley C. The Notch amino terminus regulates protein levels and Delta-induced clustering of Drosophila Notch receptors. Exp Cell Res 2005 Mar 10 304(1), 202-23.
Mok LP, Qin T, Bardot B, LeComte M, Homayouni A, Ahimou F, Wesley C. Delta activity independent of its activity as a ligand of Notch. BMC Dev Biol 2005 Mar 10 5(1), 6.
Ahimou F, Mok LP, Bardot B, Wesley C. The adhesion force of Notch with Delta and the rate of Notch signaling. J Cell Biol 2004 Dec 20 167(6), 1217-29.
Wesley CS, Mok LP. Regulation of Notch signaling by a novel mechanism involving suppressor of hairless stability and carboxyl terminus-truncated notch. Mol Cell Biol 2003 Aug 23(16), 5581-93.
Powell PA, Wesley C, Spencer S, Cagan RL. Scabrous complexes with Notch to mediate boundary formation. Nature. 2001 Feb 1; 409(6820): 626-630.
Wesley CS, Saez L. Notch responds differently to Delta and Wingless in cultured Drosophila cells. J. Biol. Chem. 2000 Mar 31; 275(13): 9099-9101.
Wesley CS, Saez L. Analysis of notch lacking the carboxyl terminus identified in Drosophila embryos. J. Cell. Biol. 2000 May 1; 149(3): 683-696.
Other Key Publications
Wesley CS. Notch and Wingless regulate expression of cuticle patterning genes. Mol. Cell. Biol. 1999 Aug; 19(8): 5743-5758.
