Developmental Biology, Genetics
University of Wisconsin–Madison
Dr. Kimble is also Vilas Professor of Biochemistry, Molecular Biology, Medical Genetics and Cell and Regenerative Biology at the University of Wisconsin–Madison.
Molecular Controls of Stem Cells and Cell Fate
Judith Kimble intended to become a physician. But in her last year as an undergraduate, she had a close encounter with the medical profession that led her in a different direction. "I found medical science to be disturbingly primitive, and doctors seemed detached and unconcerned about the human side of their profession," she says. Instead of becoming a medical student, she took a temporary job at the University of Copenhagen Medical School, where she taught medical students about the structure and function of human organs. "From this experience in Denmark, as well as from studying human embryology as an undergraduate in Berkeley, I became fascinated with basic problems in animal development," she says. Since then, she has been unraveling the controls that allow formation of an ancient organ, the gonad. Her work has led the way to understanding a variety of molecular mechanisms that control growth, differentiation, and pattern formation in all animals.
In 1974, Kimble began graduate studies at the University of Colorado with David Hirsh, who was studying Caenorhabditis elegans, a nematode and model organism. For her doctoral thesis, she mapped out the cell lineages and movements that generate the complete gonad. "Understanding the complete development of a simple organ at the level of individual cells seemed a good starting point for learning principles that control organ formation throughout the animal kingdom," Kimble says.
As a postdoc with Sir John Sulston at the MRC Laboratory of Molecular Biology in Cambridge, England, Kimble began to tackle the controls of organogenesis. Using a laser microbeam to destroy single cells, she found a special somatic cell at the very tip of the gonad, the distal tip cell, which tells adjacent germ cells (reproductive cells) how to divide. When she destroyed the distal tip cell, germ cells stopped dividing. When she moved it to a different place, germ cells started dividing in that new location. This was the first time a single cell with such an oversight function had been identified. Indeed, the distal tip cell was the first example of a cell that generates a stem cell niche ("microenvironment" that controls stem cells).
Discovery of the distal tip cell gave Kimble a powerful way to explore the controls of stem cells, which were a complete mystery in the early 1980s. "I focused on the distal tip and its control of germline stem cells, because it was an unusually simple model system of stem cell control," she explains. After Kimble became a faculty member at the University of Wisconsin in 1983, she began to unravel the genetic and molecular mechanisms responsible for germline stem cells and also to ask how germ cells decide to become sperm or egg cells. She started with the distal tip cell, figuring out both how this special cell itself is formed and how it talks to germ cells. The distal tip cell is generated by an asymmetric division controlled by a conserved regulatory pathway, called the Wnt pathway, which in turn induces production of a conserved DNA-binding protein that specifies the distal tip cell's fate. The conservation of this mechanism remains largely unknown, although in one case it is known that Wnt signaling controls a type of vertebrate cell that generates the niche for blood stem cells.
In a separate series of experiments, Kimble showed that the distal tip cell regulates germline stem cells by a different conserved pathway, called Notch signaling. Her group, along with others, identified the core components of the Notch pathway, and also contributed to learning how it transmits signals. The Notch pathway has been implicated in the growth and differentiation of many tissues in many animals, but only recently has Notch signaling been found to control stem cells in vertebrates in much the same way as it does in the nematode germline. In mammals, Notch signaling regulates the production of blood cell precursors, and defects in the pathway can lead to leukemia and other blood disorders.
In her work on the sperm/oocyte decision, Kimble identified discrete sites in messenger RNA molecules (molecules that carry information from genes to the cytoplasm) that can completely switch a germ cell from a sperm to an oocyte. In collaboration with Marvin Wickens, who is also at the University of Wisconsin–Madison and happens to be her husband, and HHMI investigator Stanley Fields, who is at the University of Washington and is a friend from her postdoc days, Kimble found FBF (fem-3 binding factor), a conserved protein that prevents specific messenger RNAs from being used to make proteins. Since finding FBF, the Kimble/Wickens team has identified several other RNA regulators that control various aspects of germ cell development. "The discovery that regulation of messenger RNA activity is so crucial for animal development was a surprise," she says. "The focus has always been on transcriptional control as developmental regulators. Now this theme has been discovered in virtually all animals where they have looked."
A big breakthrough was the realization that FBF serves as a master switch to maintain stem cells and also to regulate the sperm/oocyte decision. One of FBF's many RNA targets, fog-1, plays a dual role. Near the tip of the gonad, FBF keeps FOG-1 protein at a low level, which is required for continued cell divisions. But as daughter cells get farther and farther from the tip, FBF decreases and FOG-1 levels rise. Those high FOG-1 levels make the germ cells capable of becoming sperm. "We were stunned to learn that FBF and FOG-1 control both processes," she says. "In fact, we now know that all the RNA regulators we have uncovered control both the mitosis/meiosis decision as well as the sperm/oocyte decision." It is not yet known if this principle holds true in other organisms, because so little is known about how the sperm/oocyte decision is made in other organisms. However, proteins related to FBF control stem cells in many organisms, and proteins related to FOG-1 function in a dose-dependent manner in vertebrates, with low levels promoting mitotic divisions. The mechanisms being uncovered in nematodes are therefore likely to lead the way to understanding stem cell controls that are widely used to control animal development.
More recently, Kimble has tackled the problem of sexual dimorphism to understand how organs with different shapes, sizes, and tissues can be made from the same starting cells. The somatic gonadal progenitor cells (SGPs) can follow either a male or female program of development to generate, for example, a vas deferens or uterus. In collaboration with David Zarkower at the University of Minnesota, Kimble discovered a DNA-binding protein, FKH-6, that causes SGPs to follow the male program. In addition, she found that a well-known regulator of the cell cycle, cyclin D, is also a key regulator of sexual dimorphism. "Cyclin D is critical for coordinating multiple pathways of control at a pivotal point in development," she says. This highly conserved but poorly understood regulator couples the cell cycle and organ growth with controls of sexual dimorphism and axis formation.
Kimble's long-term goal is to unravel the complete molecular program controlling gonad formation in C. elegans. One of the best things about being a scientist, she says, is working on big questions that are initially black boxes and having those "eureka moments" when you discover a way into the problem. "Another," she says, "is having the opportunity to devote your life to following your passions."