David Kimelman

Scholar: 1990

Awarded Institution
University of Washington
Department of Biochemistry SJ-70


Research Interests

Dr. Kimelman's laboratory focuses on the molecular events involved in transforming a fertilized vertebrate egg into a complex multicellular organism. This process involves massive morphological changes caused by cellular migration, the differentiation of cells into many specialized types, and a precise and ordered spatial and temporal pattern of gene expression. Intercellular communication is a major component of these early developmental events, as first seen in the Nobel prize-winning experiments of Mangold and Spemann, which showed that much of the early amphibian embryo is determined by groups of cells directing the development of their neighbors. These intercellular signaling events are central to the development of most organisms but were difficult to study because key molecular components could not be isolated. Recently, a major series of breakthroughs has occurred with the identification of some of the key signaling molecules.

The laboratory's ultimate goal is to provide a complete description of the molecular pathway from the initial signaling events to the ordered pattern of gene expression that specifies the different regions of the early embryo. To study the genetic changes elicited by the signaling molecules, several genes containing a DNA binding region known as the homeodomain have been isolated in the frog and fish embryo. These genes are important both because they are likely to regulate other embryonic genes, and because they are expressed in unique and diverse regions of the early frog and fish embryo they can be used as markers to study the early signaling events. RNA encoding the homeodomain proteins can be misexpressed within the embryo to determine the developmental role of these genes. In addition, the normal embryonic signaling pathways can be disrupted by the expression of dominant-negative receptors, and expression of the homeodomain genes can be used to monitor the resulting changes in the embryo.

A second major area of investigation is focused on several of the signaling molecules used to direct the early development of the Xenopus embryo, and the intracellular pathways used by these signals. Studies on several of these signaling molecules have allowed us to begin to determine how the early embryo is subdivided into a variety of distinct regions, each of which expresses a unique combination of genes. These studies have led us to suggest that complex patterning in the early embryo occurs by the overlap of several intercellular signaling molecules, each of which is present in a relatively simple distribution. We refer to this process as combinatorial signaling. Our studies on the intracellular signaling pathways have identified a serine/threonine kinase, Xgsk-3, which plays a critical role in establishing the early embryonic axes. These studies will allow us to define the precise molecular events that underlie the combinatorial signaling events.

Two-headed tadpoles can be created by injecting RNA encoding a dominant-negative form of the Xgsk-3 kinase into the future ventral side of a frog (Xenopus laevis) embryo. This result shows the importance of the Xgsk-3 kinase in regulating the formation of the dorsal-ventral axis in Xenopus. For more details see Pierce, S. B. and D. Kimelman (1995) Regulation of Spemann organizer formation by the intracellular kinase Xgsk-3. Development 121, 755-765.