Gilbert Weidinger - Wnt signaling in embryonic development and organ regeneration
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Previous and current research
All animals have evolved strategies to deal with damage due to injury or disease, but the ability to regenerate lost or damaged organs and appendages varies greatly in different species. Unfortunately, humans and other mammals are quite poor at regenerating, while other vertebrates, like salamanders and fish, can efficiently re-grow lost limbs/fins and regenerate many internal organs and even the central nervous system. Currently it is a mystery why mammals can’t do what these lower vertebrates do. We hope that elucidating the molecular mechanisms that lower vertebrate use to regulate regeneration will one day result in therapies aimed at activating regenerative potential in human organs.
Zebrafish transgenic for heatshock-inducible inhibitors (hsDkk1GFP) or activators (hsWnt8GFP) of Wnt/beta-catenin signaling are ideal tools to study the roles of the Wnt signaling network at any timepoint during embryonic development or in adults
We use the zebrafish model to study the signaling pathways and the genetic regulatory circuits that regulate fin and heart regeneration. The fin is a great, simple model for studying basic cellular and molecular mechanisms of regeneration. We have found that Wnt signaling pathways play important roles in regulating fin regeneration. In particular, Wnt/beta-catenin signaling is required for formation and proliferation of the blastema, a population of stem cell-like progenitor cells that gives rise to all cell types of the regenerating fin. In contrast, beta-catenin independent Wnt signaling appears to inhibit regeneration. Currently, we are attempting to learn more about the function of these pathways in fin regeneration by identification of downstream signaling components, identification and knockdown of target genes, and by high resolution live imaging techniques.
Wnt/beta-catenin signaling is required for zebrafish fin regeneration.
Heart damage, usually caused by infarction, is a leading cause of death in humans. After cardiomyocyte death the damaged part of the myocard in humans undergoes extensive scarring and fibrosis, and no new cardiomyocytes are produced. Thus, infarction results in permanent damage to the heart. In contrast, zebrafish are able to regenerate their hearts without scarring. After amputation of up to 20% of the ventricle, the lost tissue is replaced with newly differentiating cardiomyocytes within 30 days. Currently, the molecular mechanisms regulating the formation and proliferation of progenitor cells that drive heart regeneration are completely unknown. We have found that Wnt/beta-catenin signaling is activated early during regeneration. Using transgenic zebrafish lines, we currently investigate the function of Wnt signaling in heart regeneration.
Zebrafish hearts regenerate. Within 30 days after resection of the tip of the ventricle, the blood clot sealing the wound disappears (arrows) and no scar remains.
Future prospects and goals
Characterize the role of Wnt/beta-catenin signaling in heart regeneration
Identify downstream target genes of Wnt/beta-catenin signaling in regenerative processes
Characterize the role of beta-catenin independent Wnt signaling in regeneration
Selected publications
Petros Nemtsas, Erich Wettwer, Torsten Christ, Gilbert Weidinger* and Ursula Ravens* (2009): Adult zebrafish heart as a model for human heart? An electrophysiological study. J Mol Cell Cardiol. Sep 8. [Epub ahead of print]
*corresponding authors and equal contributionYoonsung Lee, Danyal Hami, Sarah De Val, Birgit Kagermeier-Schenk, Airon A. Wills, Brian L. Black, Gilbert Weidinger and Kenneth D. Poss (2009): Maintenance of blastemal proliferation by functionally diverse epidermis in regenerating zebrafish fins. Dev. Biol. 331, 270-80.
Wolfram Goessling, Trista E. North, Sabine Loewer, Allegra M. Lord, Sang Lee, Cristi L. Stoick-Cooper, Gilbert Weidinger, Mark Puder, George Q. Daley, Randall T. Moon and Leonard I. Zon (2009): Genetic Interaction of PGE2 and Wnt Signaling Regulates Developmental Specification of Stem Cells and Regeneration. Cell 136, 1136-47.
Elly M. Tanaka and Gilbert Weidinger (2008): Micromanaging regeneration. Genes & Dev 22, 700-705.
Cristi L. Stoick-Cooper, Randall T. Moon, and Gilbert Weidinger (2007): Advances in signaling in vertebrate regeneration as a prelude to regenerative medicine. Genes Dev 21, 1292-1315.
Gilbert Weidinger
1998-2001: PhD thesis in the lab of Erez Raz at the University of Freiburg and MPI for Biophysical Chemistry, Göttingen, Germany
2002-2006: Postdoc in the lab of Randall Moon at the University of Washington, Seattle, USA
from Oct 2006: Group Leader at the BIOTEC, funded by the SFB 655
