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Wnt signaling regulates primary body axis formation across the Metazoa, with high Wnt signaling specifying posterior identity. Whether a common Wnt-driven transcriptional program accomplishes this broad role is poorly understood. We identified genes acutely affected after Wnt signaling inhibition in the posterior of two regenerative species, the planarian Schmidtea mediterranea and the acoel Hofstenia miamia, which are separated by >550 million years of evolution. Wnt signaling was found to maintain positional information in muscle and regional gene expression in multiple differentiated cell types. sp5, Hox genes, and Wnt pathway components are down-regulated rapidly after β-catenin RNAi in both species. Brachyury, a vertebrate Wnt target, also displays Wnt-dependent expression in Hofstenia. sp5 inhibits trunk gene expression in the tail of planarians and acoels, promoting separate tail-trunk body domains. A planarian posterior Hox gene, Post-2d, promotes normal tail regeneration. We propose that common regulation of a small gene set-Hox, sp5, and Brachyury-might underlie the widespread utilization of Wnt signaling in primary axis patterning across the Bilateria.

Wnt signaling regulates primary body axis formation across the Metazoa, with high Wnt signaling specifying posterior identity. Whether a common Wnt-driven transcriptional program accomplishes this broad role is poorly understood. We identified genes acutely affected after Wnt signaling inhibition in the posterior of two regenerative species, the planarian Schmidtea mediterranea and the acoel Hofstenia miamia, which are separated by >550 million years of evolution. Wnt signaling was found to maintain positional information in muscle and regional gene expression in multiple differentiated cell types. sp5, Hox genes, and Wnt pathway components are down-regulated rapidly after β-catenin RNAi in both species. Brachyury, a vertebrate Wnt target, also displays Wnt-dependent expression in Hofstenia. sp5 inhibits trunk gene expression in the tail of planarians and acoels, promoting separate tail-trunk body domains. A planarian posterior Hox gene, Post-2d, promotes normal tail regeneration. We propose that common regulation of a small gene set-Hox, sp5, and Brachyury-might underlie the widespread utilization of Wnt signaling in primary axis patterning across the Bilateria.

Planarians are flatworms capable of regenerating any missing body region. This capacity is mediated by neoblasts, a proliferative cell population that contains pluripotent stem cells. Although population-based studies have revealed many neoblast characteristics, whether functionally distinct classes exist within this population is unclear. Here, we used high-dimensional single-cell transcriptional profiling from over a thousand individual neoblasts to directly compare gene expression fingerprints during homeostasis and regeneration. We identified two prominent neoblast classes that we named ζ (zeta) and σ (sigma). Zeta-neoblasts encompass specified cells that give rise to an abundant postmitotic lineage, including epidermal cells, and are not required for regeneration. By contrast, sigma-neoblasts proliferate in response to injury, possess broad lineage capacity, and can give rise to zeta-neoblasts. These findings indicate that planarian neoblasts comprise two major and functionally distinct cellular compartments.

Regeneration requires both potential and instructions for tissue replacement. In planarians, pluripotent stem cells have the potential to produce all new tissue. The identities of the cells that provide regeneration instructions are unknown. Here, we report that position control genes (PCGs) that control regeneration and tissue turnover are expressed in a subepidermal layer of nonneoblast cells. These subepidermal cells coexpress many PCGs. We propose that these subepidermal cells provide a system of body coordinates and positional information for regeneration, and identify them to be muscle cells of the planarian body wall. Almost all planarian muscle cells express PCGs, suggesting a dual function: contraction and control of patterning. PCG expression is dynamic in muscle cells after injury, even in the absence of neoblasts, suggesting that muscle is instructive for regeneration. We conclude that planarian regeneration involves two highly flexible systems: pluripotent neoblasts that can generate any new cell type and muscle cells that provide positional instructions for the regeneration of any body region.

Regeneration requires both potential and instructions for tissue replacement. In planarians, pluripotent stem cells have the potential to produce all new tissue. The identities of the cells that provide regeneration instructions are unknown. Here, we report that position control genes (PCGs) that control regeneration and tissue turnover are expressed in a subepidermal layer of nonneoblast cells. These subepidermal cells coexpress many PCGs. We propose that these subepidermal cells provide a system of body coordinates and positional information for regeneration, and identify them to be muscle cells of the planarian body wall. Almost all planarian muscle cells express PCGs, suggesting a dual function: contraction and control of patterning. PCG expression is dynamic in muscle cells after injury, even in the absence of neoblasts, suggesting that muscle is instructive for regeneration. We conclude that planarian regeneration involves two highly flexible systems: pluripotent neoblasts that can generate any new cell type and muscle cells that provide positional instructions for the regeneration of any body region.