PROTEIN GLYCOBIOLOGY SECTION

DR. KENNETH KRAMER

Section Head

Bldg. 10, Room 8N228

Bethesda, Maryland 20892

Email: kramerk2@nhlbi.nih.gov

EDUCATION

1998-2004	Postdoctoral Fellow, Huntsman Cancer Institute, University of Utah; Salt Lake City, UT (Mentor: H. Joseph Yost)
1995-1996	Adjunct Instructor, Department of Biology, Raymond Walters College, University of Cincinnati; Cincinnati, OH (Chairman: Donald M. Meismer)
1991-1997	PhD, Department of Cell Biology, Neurobiology, and Anatomy, University of Cincinnati; Cincinnati, OH (Mentor: Richard L. Drake)
1987-1991	BS, Biology, University of Dayton; Dayton, OH

EXTERNAL PROFESSIONAL ACTIVITIES

2004-2006	Chair, Advisory Committee for Young Anatomists, American Association of Anatomists
2004-present	Scientific Consultant, Discovery Genomics; Minneapolis, MN
2004-2006	Member, Membership Committee, American Association of Anatomists
2004	Symposium Chair, “Sweet talk: Heparan sulfate proteoglycans in developmental cell signaling.” Experimental Biology. Washington, DC.

SELECTED RECENT PUBLICATIONS

Kramer, K.L., and H.J. Yost. (2003). Heparan sulfate core proteins in cell-cell signaling. Annual Review of Genetics 37, 461-84.

Kramer, K.L., and Yost, H. J. (2003). Cardiac left-right development: Are the early steps conserved? In Cold Spring Harbor Symposia on Quantitative Biology: The Cardiovascular System (Cold Spring Harbor, NY, Cold Spring Harbor Laboratory), pp. 37-43.

Kramer, K.L., Barnette, J.E., and H.J. Yost. (2002). PKCg regulates syndecan-2 inside-out signaling during Xenopus left-right development. Cell 111, 981-90.

Kramer, K.L., and H.J. Yost. (2002). Ectodermal syndecan-2 mediates left-right axis formation in migrating mesoderm as a cell-nonautonomous Vg1 cofactor. Developmental Cell 2, 115-24.

Research Summary

My long-term research interest is to understand the genes and mechanisms that regulate cardiac cell induction and migration during early vertebrate embryogenesis. Vertebrate cardiogenesis begins during gastrulation, an early stage of development in which large groups of cells coordinately move to give rise to the ectodermal, mesodermal and endodermal germ layers. By the end of gastrulation, mesodermal cardiac progenitor cells have also received information that determines their developmental fate. The gastrula-stage genes involved in the specification of cell identity and the direction of cell migration are still being identified, and little is known about the relationship between cell specification and movement. Conclusive evidence does demonstrate that cell-cell signaling is integral in controlling both cell motility and cell fate.

Recent studies in a number of model systems have demonstrated that all three of the cell-cell signaling pathways that regulate early cardiogenesis (TGFβ, Wnt, and FGF) are regulated by heparan sulfate. Heparan sulfate is an unbranched sugar chain consisting of repeateddisaccharides that are modified by sulfation and epimerization during synthesis in the golgi. The result is a finely structured chain with specific protein binding affinities. Heparan sulfate is covalently attached to core proteins in the extracellular matrix and at the cell surface, and proteins to which heparan sulfate attaches are referred to as heparan sulfate proteoglycans (HSPGs). At the cell surface, the predominant HSPGs belong to two families of core proteins: transmembrane syndecans and glycophosphatidylinositol (GPI)-linked glypicans. Characterizing both the developmental and cell biological function of HSPGs during early zebrafish development is the focus of my laboratory. Because many steps in zebrafish embryogenesis are similar to those in humans, the mechanisms and modifiers that I identify may be applicable to better understanding a wide range of cell-cell signaling events in development and disease.

Project 1: What is the role of HS core proteins during gastrulation?

From Drosophila to mouse, all three cell-cell signaling pathways that regulate early cardiogenesis are in turn regulated by HSPGs. Consequently, I think the question is not if HSPGs regulate cardiogenesis, but which specific core proteins are involved and how do they function? The partial assembly of the zebrafish genome in the last year has allowed me to clone apparently all 15 of the zebrafish HS cell surface core proteins. Interestingly, at least 13 are expressed at the beginning of gastrulation. Of these, only 2 have been described, and they both have distinct gastrula stage defects in cell migration.

Project 2: Is the HS fine structure a temporally and spatially permissive sugar code?

Covalently attached to each core protein is an unbranched chain of 50-100 disaccharide repeats; and each HS disaccharide can be modified at up to six positions, leading to an extraordinary level of sequence diversity. Commonly referred to as its fine structure, the pattern of HS modification over 2-6 disaccharides creates a specific ligand binding site. In many cases, a cell can only respond to a cell-cell signaling molecule if it has an appropriate HS fine structure at its cell surface. Recent results have shown that the HS fine structure changes during development, suggesting that a cell’s developmental fate is determined in part by which cell-cell signaling molecules bind to its HS fine structure.

Project 3: Does the core protein specify its attached HS fine structure?

The current model for HS synthesis is that the HS fine structure is determined by the complement of sulfotransferases expressed within the golgi of each cell, regardless of the core protein to which it might attach. This model is challenged by observations that modifications in the core protein can alter the interaction of HSPGs with signaling pathways. However, the HS fine structure might be regulated by the transition of the core protein through distinct combinations of sulfotransferase isoforms within the golgi.