Wnt/β-catenin signaling promotes zebrafish osteoblast dedifferentiation by wnt10a-mediated inhibition of NF-κB

Abstract

Dedifferentiation of mature cells is an essential mechanism of source cell formation for regeneration of many systems, including the zebrafish fin. Here, we use bulk and single cell RNASeq to show that osteoblast injury responses involve rapid and extensive transcriptional reprogramming, yielding a cell state that shares characteristics with embryonic osteoblasts, but also expresses many regeneration-specific genes. One gene characterizing this state is the canonical Wnt ligand wnt10a. Using genetic and transgenic perturbations, we demonstrate that wnt10a-dependent Wnt/{beta}-catenin signaling cell-autonomously induces osteoblast dedifferentiation. Loss of wnt10a or of Wnt/{beta}-catenin activity blocks the dedifferentiation program, whereas wnt10a overexpression enhances dedifferentiation and is sufficient to induce it even without injury. Wnt/{beta}-catenin signaling promotes dedifferentiation by suppressing NF-{kappa}B activity, placing it upstream of known cues whose loss causes dedifferentiation. Notably, wnt10a overexpression also stimulates cardiomyocyte dedifferentiation during zebrafish heart regeneration, revealing a conserved role in activating source-cell formation during regeneration.