Vitamin A signals play critical roles during embryonic development. In particular, heart morphogenesis depends on vitamin A signals mediated by the retinoid X receptor α (RXRα), as the systemic mutation of this receptor results in thinning of the myocardium and embryonic lethality. However, the molecular and cellular mechanisms controlled by RXRα signaling in this process are unclear, because a myocardium-restrictedRXRα mutation does not perturb heart morphogenesis. Here, we analyze a series of tissue-restricted mutations of theRXRα gene in the cardiac neural crest, endothelial, and epicardial lineages, and we show that RXRα signaling in the epicardium is required for proper cardiac morphogenesis. Moreover, we detect an additional phenotype of defective coronary arteriogenesis associated with RXRα deficiency and identify a retinoid-dependent Wnt signaling pathway that cooperates in epicardial epithelial-to-mesenchymal transformation.

Several vertebrates display the ability to regenerate parts of their body after amputation. During this process, differentiated cells reenter the cell cycle and proliferate to generate a mass of undifferentiated cells. Repatterning mechanisms act on these cells to eventually shape a regenerated tissue or organ that replaces the amputated one. Experiments with regenerating limbs/fins in newts and zebrafish have shown that members of the Msx family of homeodomain-containing transcription factors play key roles during blastema formation and patterning. Here we show that adult zebrafish have a remarkable capacity to regenerate the heart in a process that involves up-regulation of msxB and msxC genes. We present evidence indicating that heart regeneration involves the execution of a specific genetic program, rather than redeployment of a cardiac development program. Preceding Msx activation, there is a marked increase in the expression of notch1b and deltaC , which we show are also up-regulated during fin regeneration. These data suggest a role for the Notch pathway in the activation of the regenerative response. Taken together, our results underscore the use of zebrafish as a model for investigating the process of regeneration in particular and the biology of stem cells in general. Advances in these fields will undoubtedly aid in the implementation of strategies for regenerative medicine.

The cellular and molecular bases allowing tissue regeneration are not well understood. By performing gain- and loss-of-function experiments of specific members of the Wnt pathway during appendage regeneration, we demonstrate that this pathway is not only necessary for regeneration to occur, but it is also able to promote regeneration in axolotl, Xenopus, and zebrafish. Furthermore, we show that changes in the spatiotemporal distribution of β-catenin in the developing chick embryo elicit apical ectodermal ridge and limb regeneration in an organism previously thought not to regenerate. Our studies may provide valuable insights toward a better understanding of adult tissue regeneration.