Clytia hemisphaerica jellyfish, with their tetraradial symmetry, offer a novel paradigm for addressing patterning mechanisms during regeneration. Here we show that an interplay between mechanical forces, cell migration and proliferation allows jellyfish fragments to regain shape and functionality rapidly, notably by efficient restoration of the central feeding organ (manubrium). Fragmentation first triggers actomyosin-powered remodeling that restores body umbrella shape, causing radial smooth muscle fibers to converge around 'hubs' which serve as positional landmarks. Stabilization of these hubs, and associated expression of Wnt6, depends on the configuration of the adjoining muscle fiber 'spokes'. Stabilized hubs presage the site of the manubrium blastema, whose growth is Wnt/β-catenin dependent and fueled by both cell proliferation and long-range cell recruitment. Manubrium morphogenesis is modulated by its connections with the gastrovascular canal system. We conclude that body patterning in regenerating jellyfish emerges mainly from local interactions, triggered and directed by the remodeling process.

Pattern regulation in a regenerating jellyfish

The diversity of regenerative phenomena seen in adult metazoans, as well as their underlying mechanistic bases, are still far from being comprehensively understood. Reviewing both ultrastructural and molecular data, the present work aims to showcase the increasing relevance of invertebrate deuterostomes, i.e., echinoderms, hemichordates, cephalochordates and tunicates, as invaluable models to study cellular aspects of adult regeneration. Our comparative approach suggests a fundamental contribution of local dedifferentiation -rather than mobilization of resident undifferentiated stem cells- as an important cellular mechanism contributing to regeneration in these groups. Thus, elucidating the cellular origins, recruitment and fate of cells, as well as the molecular signals underpinning tissue regrowth in regeneration-competent deuterostomes, will provide the foundation for future research in tackling the relatively limited regenerative abilities of vertebrates, with clear applications in regenerative medicine.

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Beyond adult stem cells : dedifferentiation as a unifying mechanism underlying regeneration in invertebrate deuterostomes

Skin cells undergo asynthetic fission to expand body surfaces in zebrafish

Faithful establishment and maintenance of proportion is seen across biological systems and provides a glimpse at fundamental rules of scaling that underlie development and evolution. Dysregulation of proportion is observed in a range of human diseases and growth disorders, indicating that proper scaling is an essential component of normal anatomy and physiology. However, when viewed through an evolutionary lens, shifts in the regulation of relative proportion are one of the most striking sources of morphological diversity among organisms. To date, the mechanisms via which relative proportion is specified and maintained remain unclear. Through the application of powerful experimental, genetic and molecular approaches, the teleost fin has provided an effective model to investigate the regulation of scaling, size, and relative growth in vertebrate organisms. This article is categorized under: Establishment of Spatial and Temporal Patterns > Regulation of Size, Proportion, and Timing Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration Comparative Development and Evolution > Regulation of Organ Diversity.

Through veiled mirrors: Fish fins giving insight into size regulation

How body pattern is redefined to allow appropriate restoration of lost parts is a fundamental question in regenerative biology. Jellyfish, with their tetraradial symmetry, offer an unexplored paradigm for addressing patterning mechanisms during regeneration. Here we show that the extensive regenerative capacities of Clytia jellyfish do not rely on an actively maintained global patterning system, but instead emerge from local interactions. Any major injury triggers an actomyosin-powered remodeling process that restores body umbrella shape, repositions structures and generates hubs of rearranged radial smooth muscle fibers. These hubs define the position for feeding organ blastema formation. Growth of the feeding organ then requires both cell proliferation and long-range cell recruitment; its morphogenesis is directed by local interactions with the gastrovascular canal system. Such patterning systems, in which mechanically-driven remodeling precisely positions blastema formation, might represent a widespread feature of regenerating animals.

https://www.biorxiv.org/content/biorxiv/early/2019/12/23/2019.12.22.886200.full.pdf

Genetic Reprogramming of Positional Memory in a Regenerating Appendage.

Skin expansion during development is predominantly driven by growth of basal epithelial cell (BEC)-derived clonal populations, which often display varied sizes and shapes. However, little is known about the causes of clonal heterogeneity and the maximum size to which a single clone can grow. Here, we created a zebrafish model, basebow, for capturing clonal growth behavior in the BEC population on a whole-body, centimeter scale. By tracking 222 BECs over the course of a 28-fold expansion of body surface area, we determined that most BECs survive and grow clonal populations with an average size of 0.013 mm2. An extensive survey of 742 sparsely labeled BECs further revealed that giant dominant clones occasionally arise on specific body regions, covering up to 0.6% of the surface area. Additionally, a growth-induced extracellular matrix component, Lamb1a, mediates clonal growth in a cell-autonomous manner. Altogether, our findings demonstrate how clonal heterogeneity and clonal dominance may emerge to enable post-embryonic growth of a vertebrate organ, highlighting key cellular mechanisms that may only become evident when visualizing single cell behavior at the whole animal level.

Whole-body clonal mapping identifies giant dominant clones in zebrafish skin epidermis.

Vertebrate animals usually display robust growth trajectories during juvenile stages, and reversible suspension of this growth momentum by a single genetic determinant has not been reported. Here, we report a single genetic factor that is essential for juvenile growth in zebrafish. Using a forward genetic screen, we recovered a temperature-sensitive allele, pan (after Peter Pan), that suspends whole-organism growth at juvenile stages. Remarkably, even after growth is halted for a full 8-week period, pan mutants are able to resume a robust growth trajectory after release from the restrictive temperature, eventually growing into fertile adults without apparent adverse phenotypes. Positional cloning and complementation assays revealed that pan encodes a probable ATP-dependent RNA helicase (DEAD-Box Helicase 52; ddx52) that maintains the level of 47S precursor ribosomal RNA. Furthermore, genetic silencing of ddx52 and pharmacological inhibition of bulk RNA transcription similarly suspend the growth of flies, zebrafish and mice. Our findings reveal evidence that safe, reversible pauses of juvenile growth can be mediated by targeting the activity of a single gene, and that its pausing mechanism has high evolutionary conservation.

Tzu-Lun Tseng

Papers

Genetic Reprogramming of Positional Memory in a Regenerating Appendage.

Whole-body clonal mapping identifies giant dominant clones in zebrafish skin epidermis.

The RNA helicase Ddx52 functions as a growth switch in juvenile zebrafish.