Ruth Lehmann, Director

Question

The Lehmann Lab studies germ cells: the only cells in the human body that escape the deadly fate of all other cells and instead, via egg and sperm, maintain immortality through generations. What makes germ cells so different from all other cells in the body? How do germ cells first form and then interact with somatic cells so they are protected throughout lifetime?  The egg does not only pass on its DNA to the embryo but also its cytoplasm; how are cytoplasmic organelles, mitochondria and endosymbionts transmitted to and integrated into the genetic complexity of the next generation? 

Approach

Germ cells are the stem cells for the next generation. Set aside during embryogenesis from the somatic cells that form the body of the organism, germ cells impart the ability to create new life by forming the organism's gametes, or sperm and egg cells. Despite their critical role, we still know little about how germ cell fate is initiated and maintained and how germ cells evade the ultimately deadly fate of the soma. In contrast to somatic cell fates, no master-regulator transcription factor has been identified that uniquely specifies germ cell fate; instead RNA regulation plays a prominent role in germ cells that is conserved throughout the animal kingdom. 

As germ cells beget germ cells, the work in the Lehmann Lab follows the germ line life cycle.  The lab is interested in how germplasm assembles, the mechanisms that separate germ cells from somatic cells, how germ cells migrate through the embryo to reach the somatic gonad and how germ cell fate is maintained and protected throughout larval and adult life in order to generate a new organism. Because of their unique ability to renew themselves, Lehmann’s research takes advantage of the opportunities germ cell biology poses to understand the cellular mechanisms of totipotency and the challenges associated with immortality.

Lehmann and her lab have had a long-standing interest into how maternally inherited RNAs are enriched and specifically regulated within germline specific RNA-protein (RNP) granules.  Early on the lab discovered that germplasm RNAs are translationally repressed in the somatic regions, and that localization to germ granules is linked to their translational activation. The critical sequences for both RNA localization to and translational regulation in germ granules are located in the 3’UTR of germplasm RNAs. In recent studies, Lehmann and colleagues applied highly quantitative approaches to analyze RNA organization in germ granules in vivo at the single molecule level. They found that multiple mRNA copies of the same gene self-organize into “homotypic clusters” and occupy defined positions within the granule; while transcript-specific, this sorting mechanism is 3’UTR-independent.

In most species, germ cells are born far away from the somatic tissues of the gonad and thus have to migrate along and through tissues. Lehmann's lab has used intensive, high-throughput genetic approaches in Drosophila to identify the critical players of germ cell migratory pathways. She and her colleagues identified and characterized three major signaling pathways regulating different stages of germ cell migration. They showed that  GPCR activation triggers polarization and directed dispersal of early embryonic germ cells, that a repulsion mechanism mediated by lipid phosphate phosphatase sorts and repels germ cells away from the midline and finally that a cascade of catalytic steps downstream of the enzyme HMG CoA reductase attracts germ cells to the somatic gonads. To observe the cellular events of migration deep within the living organism, the Lehmann Lab is focused on developing high-resolution imaging approaches with biosensors and optogenetics for germ cells.  

Another area of interest in the Lehmann Lab concerns gonad morphogenesis, specifically oogenesis.  Once primordial germ cells (PGCs) reach the somatic gonad, they proliferate but do not differentiate until late larval-pupal stages. The Lehmann Lab found that during the proliferation phase in the early stages of larval gonad development, a negative feedback loop coordinates PGC proliferation and somatic cell growth such that gonads which received too few germ cells can catch up and those with too many slow down growth. To identify all major networks required for germ line stem cells (GSC) self-renewal and differentiation, they conducted a comprehensive, transcriptome-wide  genetic study using germline-specific RNAi in collaboration with the Hannon lab at Cold Spring Harbor Labs. These functional studies were recently complemented by single cell RNA sequencing to uncover all known cell types of the developing larval ovary and in the adult. With these comprehensive and large-scale data sets the lab is poised to assign developmental networks for germ cell differentiation and gonad morphogenesis. 

A new interest in the Lehmann Lab is the transmission of mitochondria and cytoplasmic symbionts. Mitochondria are passed to the next generation exclusively through the female germline. As mitochondria (mt) carry their own genome, and in contrast to the nuclear genome, are not equipped with robust recombination or proof-reading mechanisms, mutations accumulate in mt DNA through generations. The lab found that developmentally-regulated mitochondrial fragmentation during early stages of germ cells differentiation in the adult triggers selection of defective mitochondria via mitophagy and selective mtDNA replication. In parallel to studies on mitochondrial inheritance, the lab started to explore Wolbachia, an intracellular bacterium that is capable of infecting a remarkably large range of insect hosts. Wolbachia infection appears to protect the host from a variety of diseases caused by viruses, such as dengue fever and zika. The mechanisms underlying this protection are unclear, but effectiveness of the antiviral response is closely linked to Wolbachia density. Like mitochondria, Wolbachia are only transmitted via the female germline. In an unbiased, transcriptome-wide RNAi screen in infected Drosophila tissue culture cells, the Lehmann Lab quantitatively assessed changes in Wolbachia levels and identified host factors that alter Wolbachia growth and transmission. In future studies Lehmann is interested in addressing a critical bottleneck for studies of mitochondria and Wolbachia interactions with their host: the inability to specifically manipulate their genomes.  
 

Bio

Lehmann earned her undergraduate degree and a PhD in biology with Christiane Nüsslein-Volhard from the University of Tübingen, in her home country of Germany. She has conducted research at the University of Washington, the University of Freiburg, the Max Planck Institute for Developmental Biology and the Medical Research Council Laboratory of Molecular Biology in Cambridge, England, She was a Member of the Whitehead Institute Member and on the faculty of MIT from 1988-1996. She then moved to New York University (NYU), where she served in a number of leadership roles specifically as the Laura and Isaac Perlmutter Professor of Cell Biology and director of the Skirball Institute of Biomolecular Medicine (2006-2020) and from 2014-2020 as the Chair of the Department of Cell Biology at NYU’s Grossman School of Medicine. She also became an investigator with the Howard Hughes Medical Institute in 1990 and again in 1997. In 2020, Lehmann took on the role of president and director of the Whitehead Institute. She has received national and international recognition including election to the National Academy of Sciences as Foreign Associate in 2005 and election as Associate Member of the European Molecular Biology Organization in 2012. She is currently editor-in-chief of the Annual Review of Cell and Developmental Biology and will serve as president of the American Society for Cell Biology starting in 2021.