Elly Tanaka - Animal Models of Regeneration


1987-1993  PhD, Department of Biochemistry, University of California, San Francisco, USA
 
 1994-1999 Post-doctoral fellow, Ludwig Institute for Cancer Research, London and University College, London, UK, Department of Biochemistry and Molecular Biology

1999-2007 Group Leader at the Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany 

since 2008 Professor for Animal Models of Regeneration, CRTD

since 2014 Director, DFG Research Center / Cluster of Execellence 'Regenerative Therapies'

 

Previous and current research

 Coaxing somatic and embryonic stem cells to regenerate damaged tissue is currently a major focus of biomedical research. Although mammals are relatively poor in this attribute, a wide variety of metazoans display tremendous regenerative capacity. Our aim is to understand the basic cellular and molecular principles that drive regeneration in a model vertebrate with the ultimate goal of understanding which mechanisms are limiting in mammals. In vertebrates, the most robust regeneration is found in the Caudata (salamanders) that are able to regenerate their limbs, tails, spinal cord, eye and jaw. Specifically, the Axolotl (Ambystoma mexicanum) is the best model vertebrate system for regeneration.Using this model, we seek to define, 1) which tissues give rise to the progenitor cells that drive regeneration, 2) whether this process occurs via the activation of a resident stem cell, or through dedifferentiation, 3) whether the progenitor cells for regeneration represent lineage restricted or pluripotent cells. Using this knowledge we are pursuing strategies to identify the extracellular molecules, generated upon limb and tail injury, that stimulate the mature tissue to produce progenitor cells. We further want to know how the mature tissue is reprogrammed during regeneration to give rise to progenitor cells.
 
 Probing the origin and pluripotency of blastema cells by tracing cell fate in vivo
 We developed the methods to trace single cells during tail regeneration in Ambystoma mexicanum. These experiments have so far resulted in two scientific findings. First, by following the fate of single muscle fibers during tail regeneration, we demonstrated that the dedifferentiation of syncytial muscle fibers into proliferating mononucleate cells occurs during regeneration and generates approximately 13% of the blastema. Second, by following the fate of neural stem cells in the spinal cord and correlating this with the expression of molecular markers,, we have seen that neural progenitors usually remain in distinct domains during regeneration.  This means that the spinal cord has a spatial coordinate system, and the neural progenitors usually remain within certain spatial constraints.  The exception, however, is the tip of the regenerating spinal cord, where cells seem to acquire a more flexible, multipotent state.


 Molecular assays for muscle dedifferentiation
 Dedifferentiation is a crucial step to start regeneration. The two steps of muscle dedifferentiation, cell cycle re-entry from the differentiated state and fragmentation of the syncytium into mononucleate cells, can be reconstituted using cultured myotubes. We are using these in vitro assays to identify the extracellular factors that initiate dedifferentiation.
 
 Development of tools to study regeneration
 We are developing the molecular markers and gene sequence information to study the important molecular players of regeneration. We undertook our own EST sequencing project. To date, we have sequenced 18,000 ESTs from two Ambystoma mexicanum cDNA libraries and have assembled a database for comparing clone representation in the two libraries. We are currently developing the methods to screen genes that will serve as useful markers for spinal cord regeneration by in situ hybridisation to sections. Finally, in collaboration with the protein expression unit, we are using high-throughput methods to produce GST-fusion proteins of C-terminal fragments of relevant genes for monoclonal and polyclonal antibody production.
 

 

 Future prospects and goals

  • Molecular mechanism underlying lineage switching from a neural to a muscle cell fate during regeneration
  • Biochemical purification of the cell cycle re-entry factor during dedifferentiation
  • Expression cloning of the dedifferentiation-associated fragmentation factor
  • Epigenetic reprogramming that occurs to initiate the regenerative process

 

Group Members

List of group members

 Selected publications

Kragl M., Knapp D., Nacu E., Khattak S., Maden M., Epperlein HH., Tanaka EM., Cells keep a memory of their tissue origin during axolotl limb regeneration. 2009 Nature (in press)

Lööf S., Straube WL., Drechsel D., Tanaka EM., Simon A. Plasticity of mammalian myotubes upon stimulation with a thrombin-activated serum factor. Cell Cycle 2007; 6:1096-101

Mchedlishvili L, Epperlein HH, Telzerow A, Tanaka EM.  A clonal analysis of neural progenitors during axolotl spinal cord regeneration reveals evidence for both spatially restricted and multipotent progenitors.  Development. 2007; 134:2083-93.
 
 Sobkow L, Epperlein HH, Herklotz S, Straube WL, Tanaka EM. A germline GFP transgenic axolotl and its use to track cell fate: dual origin of the fin mesenchyme during development and the fate of blood cells during regeneration. Dev Biol. 2006; 290:386-97.
  
 Mercader N, Tanaka EM, Torres M. Proximodistal identity during vertebrate limb regeneration is regulated by Meis homeodomain proteins. Development. 2005; 132:4131-42. 
 
 Schnapp E, Kragl M, Rubin L, Tanaka EM. Hedgehog signaling controls dorsoventral patterning, blastema cell proliferation and cartilage induction during axolotl tail regeneration. Development. 2005;132:3243-53. 
 
 Echeverri K, Tanaka EM. Proximodistal patterning during limb regeneration. Dev Biol. 2005;279:391-401.

Schnapp E, Tanaka EM. Quantitative evaluation of morpholino-mediated protein knockdown of GFP, MSX1, and PAX7 during tail regeneration in Ambystoma mexicanum. Dev Dyn. 2005;232:162-70.
  
 Straube WL, Brockes JP, Drechsel DN, Tanaka EM. Plasticity and reprogramming of differentiated cells in amphibian regeneration: partial purification of a serum factor that triggers cell cycle re-entry in differentiated muscle cells. Cloning Stem Cells. 2004;6:333-44.
  
 Habermann B, Bebin AG, Herklotz S, Volkmer M, Eckelt K, Pehlke K, Epperlein HH, Schackert HK, Wiebe G, Tanaka EM. An Ambystoma mexicanum EST sequencing project: analysis of 17,352 expressed sequence tags from embryonic and regenerating blastema cDNA libraries. Genome Biol. 2004;5:R67.
  
 Putta S, Smith JJ, Walker JA, Rondet M, Weisrock DW, Monaghan J, Samuels AK, Kump K, King DC, Maness NJ, Habermann B, Tanaka E, Bryant SV, Gardiner DM, Parichy DM, Voss SR. From biomedicine to natural history research: EST resources for ambystomatid salamanders. BMC Genomics. 2004;5:54.
 
 Echeverri, K., Tanaka, E. M. (2002): Ectoderm to mesoderm lineage switching during Axolotl tail regeneration. Science, 298: 1993-6
 
 Echeverri, K., Clarke, J. W. C., Tanaka, E. M. (2001): In vivo imaging implicates muscle fiber dedifferentiation as a significant contributor to the regenerating tail blastema. Developmental Biology, 236: 151-64

Reviews
 
 Tanaka EM and Galliot, B. Triggering the regeneration and tissue repair programs, Development, 2009.  136: 349-353.
 
 Kragl M, Knapp D, Nacu E, Khattak S, Schnapp E, Epperlein HH, Tanaka EM.  Novel insights into the flexibility of cell and positional identity during urodele limb regeneration.  Cold Spring Harbor Quant Symp. 2008. 2008 Nov 26
  
 Tanaka EM, Weidinger G.  Micromanaging Regeneration.  Gene Dev.  2008.  22:700-5
  
 Tanaka EM, Weidinger G.  Heads or tails: can Wnt tell which one is up?  Nat Cell Biol. 2008. 10:122-4.
  
 Straube WL, Tanaka EM.  Reversibility of the Differentiated State: Regeneration in Amphibians.  Artificial Organs.  2006; 30: 743-755.
  
 Tanaka EM. Cell differentiation and cell fate during urodele tail and limb regeneration. Curr Opin Genet Dev. 2003;13:497-501.
  
 Tanaka EM.  Regeneration: if they can do it, why can't we?  Cell. 2003;113:559-62.
  
 Echeverri K, Tanaka EM. Electroporation as a tool to study in vivo spinal cord regeneration. Dev Dyn. 2003;226:418-25.
  
 Echeverri K, Tanaka EM. Mechanisms of muscle dedifferentiation during regeneration. Semin Cell Dev Biol. 2002;13:353-60.
  
 Tanaka EM, Gann AF. Limb development. The budding role of FGF. Curr Biol. 1995;5:594-7.
  
 Tanaka E, Sabry J.  Making the connection: cytoskeletal rearrangements during growth cone guidance. Cell. 1995;83:171-6.
  
  
 Book Chapters
  
 Voss R, Tanaka EM.  The Axolotl as an emerging system.  in Emerging Model Systems.  Cold Spring Harbor Laboratories, in press. 
  
 Tanaka, EM.  2008.  Skeletal muscle reconstitution during limb and tail regeneration in amphibians:  Two contrasting mechanisms  in Skeletal Muscle Repair and Regeneration.  pp. 181-198.  Ed. S. Schiaffino and T. Partridge.   Springer Science.

Last Modified: 30/10/2014