Background: The molecular mechenism controls epimorphic regeneration is a subject of extensive investigation.A small set of evolutionarily conserved molecular pathways such as Wnt, BMP, FGF, Notch and RA signaling are involved in regulating this process.However, the driving force for tissue regeneration remains unknown.Here we use the feather follicle to dissect the guiding force for tissue / organ regeneration.Methods: To gain insight into the molecules encoded in the DP, a critical component for feather regeneration, we quantitatively profiled the gene expression by using next-generation sequencing technology.Functional perturbation of feather regeneration was performed by overexpression, siRNA delivery and antibody blocking.Further evaluation of molecular functions was done in Xenopus embryo and in cell reporter assays.Results: The feather DP expressed high level of Dkk2 / Dkk3 / Frzb, presumably encoding Wnt signaling inhibitors.On the other hand, Wnt ligands such as Wnt4 / Wnt5a / Wnt6 were mainly expressed in the removable upper portion of the follicle.During regeneration, the Wnt ligands were removed or diminished to a very low level then gradually recover, while the inhibitors dropped initially, then also increased to previous levels.The expression pattern suggest a feedback loop between Wnt inhibitors in the DP and Wnt ligands in the feather epithelium.Biochemical analysis revealed Dkk2 / Dkk3 / Frzb are all Wnt target genes, and functional experiments suggest these inhibitor molecules were important for feather regeneration and maintaining the DP cell property and feather axis.Conclusion: Our results suggested a Wnt/Dkk feedback loop encoded in different compartments of the feather follicle drives feather regeneration.This work provides an elegant demonstration of systems modeling of tissue regeneration .