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Beyer
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Corbeil
Hoflack
Müller
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Seidel
Stewart
Weidinger


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Weidinger group

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Our group focuses on two aspects of developmental biology:

(1) The extracellular signaling mechanisms that regulate zebrafish fin
and heart regeneration

(2) Downstream mediators and modulators of Wnt/beta-catenin signaling

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 vertebrates use to regulate regeneration will one day result in therapies aimed at activating regenerative potential in human organs.

Adult zebrafish efficiently regenerate many organs and structures after injury.

Fin regeneration

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.

Wnt pathway mediators and modulators

The Wnt/beta-catenin signaling pathway is of enormous importance for the regulation of animal cell fate and proliferation during many processes in embryonic development and in the function of adult stem cells. However, in many contexts it is unclear how Wnt signaling mediates these effects, since few direct targets genes of the pathway are known. We are therefore interested in identifying genes that are regulated by Wnt/beta-catenin signaling not only during fin regeneration, but during embryogenesis as well. Genes that are regulated by Wnt signaling in many tissues are likely to represent feedback modulators of the pathway. We have identified several of these general Wnt targets and are studying their function during embryogenesis and during adult fin regeneration.

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.

Heart 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.