Ruth Lehmann, PhD
Director, Kimmel Center for Stem Cell Biology
Director, Skirball Institute of Biomolecular Medicine
Laura and Isaac Perlmutter Professor of Cell Biology
Stem Cell Biology, Cell Migration, Cell Polarity, Meiosis, Morphogenesis, Segmentation and Pattern Formation
Primordial Germ Cells, Germ Line Stem Cells, Cell Migration, Translational Regulation, Transposable Elements, piRNA
Skirball Institute of Biomolecular Medicine
New York University School of Medicine
540 First Ave. 4th floor
New York, NY 10016
Tel: (212) 263-8071
Fax: (212) 263-0614
Primordial germ cells are the stem cells of the next generation. In contrast to many other cell types of the body that make up the soma no conserved master transcriptional regulator has been identified that is sufficient to specify germ cells. Rather germ cell specification requires the transcriptional repression of somatic fate and the correct expression or localization of conserved, germ line specific RNA regulators that coordinate germ line programs. In most organisms, primordial germ cells (PGCs) are set-aside early during embryogenesis. Subsequently, PGCs migrate through the embryo, associate with somatic gonadal cells and form the embryonic gonad. Here, PGCs become germline stem cells that eventually give rise to sperm and egg. We developed assay systems in Drosophila that allow us to conduct large-scale genetic and molecular screens to identify factors required for (1) PGC formation and specification, (2) PGC migration, (3) stem cell maintenance and differentiation. Here, we are particularly interested in determining how germ cells maintain and promote their immortality, we are studying how germ cells prevent somatic differentiation, cope with transposable element activity and fight off or entertain mutualistic relationships with pathogens.
1. Germ cell formation and transcriptional silencing
The molecular mechanisms that set aside germ cells and somatic cells in Drosophila are very different: somatic cells form as a polarized epithelium while germ cells develop by budding within the specialized germplasm. Our goal is to understand how the architecture of germplasm contributes to germ cell functions. We recently determined the cellular mechanism by which early germ cells are formed. This mechanism is strikingly different both at the cellular and molecular level from the cellularization event that leads to the formation of all cells in the soma. Germ cells form via constriction of two orthogonal furrows. Interestingly, one of these furrows does not require mitotic spindle mediated activation of the constriction machinery, suggesting a new molecular mechanism that can trigger membrane constriction. We have identified the conserved Germ cell-less protein in playing an instructive role in this event.
2. Germ cell migration.
PGCs form at the posterior pole of the Drosophila embryo and are carried inside the embryo during gastrulation in juxtaposition to the posterior midgut. Subsequently, PGCs migrate actively through the midgut epithelium and navigate along the midgut toward the mesoderm, where they associate with somatic gonadal precursors to form the embryonic gonad. At least three signaling pathways regulate germ cell migration: a) The G protein coupled receptor Tre1 controls transepithelial migration through the posterior midgut. b) Wunen and Wunen 2, two lipid phosphate phosphatase, affect germ cell repulsion and survival. c) The isoprenylation via the HMGCoA reductase pathway regulates the production of a germ cell attractant. Complementary to genetic and biochemical studies we are using live imaging to develop a cellular view of germ cell chemoattraction and repulsion and have developed in vitro migration assays to identify the molecules involved in germ cell chemotaxis and survival. Recent results suggest that PGCs take advantage of epithelial restructuring in the midgut at the onset of their migration. Consequently, weakening epithelial adhesion leads to precocious PGC migration.
3. Germ line stem cells
The germ line is an ideal system to study stem cell maintenance and differentiation. We are interested in understanding how PGCs populate the gonad, how they are prevented from differentiation during larval stages and how, as germ line stem cells (GSCs), they are maintained in the adult. Most recently we have conducted a systematic screen of germ line expressed genes for GSC renewal and differentiation phenotype. Using RNAi targeting the transcripts of these genes specifically in the germ line, we identified 116 lines that affect GSC differentiation, where germ line cells fail to differentiate and 75 lines showed a GSC maintenance and survival phenotype, without affecting survival in other somatic tissues. We are no in the process is confirming these hits with additional RNAi lines and genomic mutants.
Research is supported by NIH and HHMI
- CinalliRM, and Lehmann R. (2013) A spindle independent cleavage pathway controls germ cell formation in Drosophila. Nat Cell Biol. 2013 Jul;15(7):839-45. PMID: 23728423
- Seifert JRK., and Lehmann R. (2012) Drosophila primordial germ cell migration requires epithelial remodeling of the endoderm. Development Jun;139(12):2101-6. PMID: 22619387
- Lehmann R. (2012) Germline stem cells: origin and destiny. Cell Stem Cells June 10; 10 729-739. PMID: 22704513
- Hurd TR., DeGennaro M., and Lehmann R. (2012) Redox regulation of cell migration and adhesion. Trends Cell Biol. Feb; 22(2):107-15. PMID: 22209517
- DeGennaro M., Hurd TR., Biteau B., Jasper H., Siekhaus D., and Lehmann R. (2011) Peroxiredoxin stabilization of DE-cadherin promotes primordial germ cell adhesion. Dev. Cell 20, 233-243. PMID: 21316590
- Rangan P, Malone CD, Navarro C, Newbold SP, Hayes RS, Sachidanandan R, HannonGJ, LehmannR. (2011) piRNA production requires heterochromatin formation in Drosophila. Current Biology Aug 23;21(16):1373-9. PMID: 21820311
- ZampariniAL, Davis MY, MaloneCD, VieiraE, ZavadilJ, Sachidanandan R, HannonGJ, LehmannR. (2011) Vreteno, a gonad-specific protein, is essential for germline development and primary piRNA biogenesis in Drosophila. Development Sep;138(18):4039-50. PMID: 21831924
- Richardson BE, Lehmann R. (2010) Mechanisms guiding primordial germ cell migration: strategies form different organisms. Nat Rev Mol Cell Biol. Jan;11(1):37-49. PMID: 20027186
- RenaultA.D., KunwarP.S. and LehmannR. (2010) Lipid phosphate phosphatase activity regulates dispersal and bilateral sorting of embryonic germ cells in Drosophila Development 137(11):1815-23. PMID: 20431117
- Siekhaus D., Haesemeyer M., Moffitt O., and Lehmann R. (2010) RhoL controls invasion and Rap1 localization in Drosophila hemocytes. Nature Cell Biology 12(6):605-10. PMID: 20495554
- Liu H., Wang JY., Huang Y., Li Z., Gong W., Lehmann R. and Xu RM. (2010) Structural Basis for Methylarginine-dependent Recognition of Aubergine by Tudor. Genes & Development 24(17):1876-81. PMID: 20713507
- Biteau B, Karpac J, Supoyo S, Degennaro M, Lehmann R, Jasper H. (2010) Lifespan extension by preserving proliferative homeostasis in Drosophila. PLoS Genetics;6(10):e1001159. PMID: 20976250
- Seifert JRK and Lehmann R. (2010) Live Imaging of Drosophila Development in Optical Imaging Techniques CSH Press pp23-48.