Gilbert Weidinger

Wnt signaling in embryonic development and organ regeneration

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.

Fig.1 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.

Fig 2 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.

Fig 3 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.

Current projects

• Identification of molecular mechanisms regulating bone plasticity during fin regeneration

• Molecular regulation of heart regeneration

• Modulators and downstream effectors of Wnt/beta-catenin signaling during embryogenesis and regeneration

About

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 of the TU Dresden, funded by the SFB 655

Selected publications

Franziska Knopf, Christina Hammond, Avinash Chekuru, Thomas Kurth, Stefan Hans, Christopher W. Weber, Gina Mahatma, Shannon Fisher, Michael Brand, Stefan Schulte-Merker and Gilbert Weidinger. Bone regenerates via dedifferentiation of osteoblasts in the zebrafish fin. Dev. Cell 20, 713-724.

Kristin Schnabel, Chi-Chung Wu, and Gilbert Weidinger (2011): Regeneration of cryoinjury induced necrotic heart lesions in zebrafish is associated with epicardial activation and cardiomyocyte proliferation. PLOS One 6, e18503.

Franziska Knopf, Kristin Schnabel, Christa Haase, Katja Pfeifer, Konstantinos Anastassiadis, and Gilbert Weidinger (2010): Dually-inducible TetON systems for tissue-specific conditional gene expression in zebrafish. PNAS 107, 19933-19938.

Petros Nemtsas, Erich Wettwer, Torsten Christ, Gilbert Weidinger* and Ursula Ravens* (2010): Adult zebrafish heart as a model for human heart? An electrophysiological study. J Mol Cell Cardiol. 48, 161-171. * corresponding authors and equal contribution

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.

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