Developmental Biology, Genetics
New York University
Dr. Lehmann is also Laura and Isaac Perlmutter Professor of Cell Biology, the director of the Skirball Institute of Biomolecular Medicine, and the chair of the Department of Cell Biology at New York University School of Medicine.
Germ Cells Are Forever
The survival of a species depends on its germ cells, which are set aside in the embryo and make eggs or sperm later in life. Ruth Lehmann has devoted her career to determining how germ cells are produced, how they find their way into the gonads, and how they maintain their identity in adult organisms.
Disappointed with her "rather boring" undergraduate education in Germany and inspired by her "green spirit," Ruth Lehmann went to the University of Seattle in 1977 as a Fulbright scholar. At a conference the next year, she heard a young biologist, Christiane Nüsslein-Volhard (who would earn a Nobel Prize in 1995), describe the effects of molecular gradients on fruit fly development. "I thought, 'This is what I want to do,' because it combined my interest in math with developmental genetics," Lehmann says. On returning to Germany to study in Freiburg, she spent most weekends in Nüsslein-Volhard's lab in nearby Heidelberg, studying the group's mutant embryos.
In 1981, Nüsslein-Volhard moved to Tübingen, and Lehmann joined her the following year. When the small group began to look at maternal genes that affected embryonic development, one big puzzle was how the regions where the head or tail will form are already specified in the mother during egg production. By screening mutant flies, the group identified several maternal genes that determined which parts of the embryo would become the fly's front and rear ends. Choosing the tail end (the posterior pole), Lehmann focused on a gene called oskar, showing that its integrity in the mother is necessary for the development of germ cells in the embryo's posterior region.
While Lehmann was still a Ph.D. student, she was offered a position at MIT. Frustrated by the outlook for women in German universities, she accepted the offer and then spent a year in Cambridge, England, learning molecular biology techniques.
During her 8 years at MIT, Lehmann explored a novel way in which maternal genes can control embryonic development. The oskar and nanos genes didn't deposit protein into the egg, she found; they deposited RNA, which was localized at the posterior pole. Thus, when Lehmann and her postdoctoral fellow Anne Ephrussi inserted oskar RNA into the anterior pole of an egg, germ cells developed there instead of at the posterior pole. Similarly when Liz Gavis, another postdoc in the group, inserted the nanos gene at the anterior pole, posterior structures such as the abdomen developed there instead of the usual head. It was known that germ cells in Drosophila form in a specialized cytoplasm, but it had been difficult to dissect the process mechanistically. "Our results showed that Oskar protein was sufficient to make germ plasm and germ cells somewhere else and thus gave us a first glimpse of how germ cells may become different from the other cells in the body," Lehmann says. These findings also emphasized the importance of RNA localization in determining cell fate. At that time, this concept was just emerging from studies of frog and fly oocytes.
Lehmann later discovered a second mechanism for regulating RNA. While nanos and oskar RNA molecules were found everywhere in the oocyte and embryo, they were translated only at the posterior pole, where RNA was localized and where Oskar and Nanos proteins were needed for germ cell formation and posterior patterning. More recently, several other systems that restrict the translation of RNA to discrete locations have been discovered. "It's an effective way of regulating genes within a single cell, such as an oocyte or a neuron," Lehmann points out, adding that a fertilized egg has only one set of genes and therefore isn't amenable to differential transcription to make one region of the egg different from another.
After moving to New York University in 1996, Lehmann became interested in the behavior of germ cells, which must migrate from the embryo's posterior pole to enter the gonads. By screening for mutants with abnormal gonadogenesis, she identified several essential genes. One encoded a G protein–coupled receptor, which spans the outer membrane of cells. By transmitting certain extracellular signals into the interior of germ cells, this receptor helps initiate migration and enables the cells to push through the gut epithelium on its way to the gonad. Lehmann also discovered that gradients of lipid molecules act as road signals that point germ cells toward the gonads. "What was surprising about these results was that we didn't find some of the signals that people had predicted and shown to guide other cells like neurons," Lehmann says. "We actually found novel signaling pathways, like those using lipids."
More recently, Lehmann's group has been asking what happens to germ cells when they reach the gonad and become germline stem cells in the adult. Germline stem cells divide throughout adult life to produce a daughter cell that differentiates and a replacement stem cell. Lehmann found that some of the same genes, such as nanos, that are needed for germ cell development in the embryo, are also needed in the adult to maintain the "stem cell fate." In contrast to other stem cells in the adult, which can regenerate several cell types within a tissue, germline stem cells give rise to only one cell type: egg or sperm. But these cells are then able to generate a whole new organism. Lehmann says her group is searching for a core set of genes— "the germ genes"—that make these cells so different from the other cells in the body. "We know that some of the key genes, such as nanos and pumilio, encode RNA-binding proteins," Lehmann says. "And we think they're regulating the translation of target genes that may be effectors of germline fate."
In the future, Lehmann hopes to spy on cells with a microscope to see what happens as germ cells migrate and become stem cells in the gonad. She wants to know if certain molecules localize to, say, the front of the cell, to determine the direction of migration. How the G proteincoupled receptor initiates migration and how germ cells stop migration and become stem cells is another question. And how do the "germ genes" the group is just beginning to identify collaborate to provide unique developmental programs for germ cells, such as the control of germ cell migration, while keeping germ cells immortal and fit for the next generation? Lehmann thinks up such questions not only in the lab but also when she is cross-country skiing in the winter or jogging and hiking in the summer. "My joy is the outdoors," she explains. "That is a good time to think about germ cells."