Wnt/β-Catenin Signaling Defines Organizing Centers that Orchestrate Growth and Differentiation of the Regenerating Zebrafish Caudal Fin

Abstract

Zebrafish regenerate their fins via the formation of a population of progenitor cells, the blastema. Wnt/β-catenin signaling is essential for blastemal cell proliferation and patterning of the overlying epidermis. Yet, we find that β-catenin signaling is neither active in the epidermis nor the majority of the proliferative blastemal cells. Rather, tissue-specific pathway interference indicates that Wnt signaling in the nonproliferative distal blastema is required for cell proliferation in the proximal blastema, and signaling in cells lining the osteoblasts directs osteoblast differentiation. Thus, Wnt signaling regulates epidermal patterning, blastemal cell proliferation, and osteoblast maturation indirectly via secondary signals. Gene expression profiling, chromatin immunoprecipitation, and functional rescue experiments suggest that Wnt/β-catenin signaling acts through Fgf and Bmp signaling to control epidermal patterning, whereas retinoic acid and Hedgehog signals mediate its effects on blastemal cell proliferation. We propose that Wnt signaling orchestrates fin regeneration by defining organizing centers that instruct cellular behaviors of adjacent tissues.

Wnt/ß-catenin signaling is required for radial glial neurogenesis following spinal cord injury

“…Canonical Wnt gene expression is detected at the leading edge of the blastema in the regenerating zebrafish caudal fin as early as 6 hours post amputation (hpa), while Wnt reporter activity is detectable by 12hpa (Stoick-Cooper et al, 2007; Wehner et al, 2014). Additionally, in the regenerating Xenopus limb bud, Xwnt3a is detectable in the blastema by 3 days post amputation (Yokoyama et al, 2007).…”

“…In the regenerating zebrafish caudal fin, Wnt/ß-catenin signaling functions to regulate blastemal cell proliferation and osteoblast differentiation (Wehner et al, 2014). Furthermore, in the zebrafish retina Wnt/ß-catenin activity is necessary for Müller glia to re-enter the cell cycle, dedifferentiate, and generate multiple cell types following injury (Meyers et al, 2012; Ramachandran et al, 2011).…”

Mechanisms of urodele limb regeneration

“…The Wnt/β‐catenin signaling pathway is necessary for fin ray regeneration. Wnt signaling in the distal blastema of the ray has been found to set up organizing centers in the proximal blastema and epidermis that control epidermal patterning via Fgf and BMP signaling, and blastema proliferation by RA and hedgehog signals (Wehner et al., 2014). Whether there is a master organizer such as a Wnt/β‐catenin signaling region is unknown.…”

Reconsidering regeneration in metazoans: an evo-devo approach

“…For instance retinoic acid (RA), FGFs and Wnts are highly conserved signaling pathways involved in a multitude of cellular processes that range, for example, from regulation of cell proliferation or apoptosis to tuning stem cell behavior (Clevers et al, 2014). It has been shown that Wnts for example, coordinate tissue dedifferentiation and also tune progenitor cells during structure regeneration in cnidarians, planarian, amphibians and teleosts (Guder et al, 2006;Reddien, 2011;Jager et al, 2013;Lin et al, 2013;Wehner et al, 2014). Positional information of blastema cells during limb regeneration in amphibians is affected by retinoids, mainly by influencing the expression of homeobox genes (Gardiner et al, 1995;Mercader et al, 2005).…”