Calcineurin Controls Proximodistal Blastema Polarity in Zebrafish Fin Regeneration
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ABSTRACT:
PROVIDER: PRJNA669701 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12831463_1.fastq.gz | Fastqsanger.gz | |||
| SRR12831463_2.fastq.gz | Fastqsanger.gz | |||
| SRR12831464_1.fastq.gz | Fastqsanger.gz | |||
| SRR12831464_2.fastq.gz | Fastqsanger.gz | |||
| SRR12831465_1.fastq.gz | Fastqsanger.gz |
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Project description:Planarian flatworms regenerate their heads and tails from anterior or posterior wounds and this blastema regeneration polarity is controlled by Wnt/β-catenin signaling. It is well known that a regeneration blastema of appendages of vertebrates such as fish and amphibians grows distally. However, it remains unclear whether a regeneration blastema in vertebrate appendages can grow proximally. Here, we show that a regeneration blastema in zebrafish fins can grow proximally along the proximodistal axis by calcineurin inhibition. We used fin excavation in adult zebrafish to observe the unidirectional regeneration, from the anterior cut edge (ACE) to the posterior cut edge (PCE) of the cavity and this unidirectional regeneration polarity occurs as the PCE fails to build blastemas. Furthermore, we found that calcineurin activities in the ACE were greater than in the PCE. Calcineurin inhibition induced the PCE blastemas, and calcineurin hyperactivation suppressed fin regeneration. Collectively, these findings identify calcineurin as a molecular switch to specify the PCE blastema of the proximodistal axis and regeneration polarity in zebrafish fin.
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Project description:Planarian flatworms regenerate their heads and tails from anterior or posterior wounds and this regenerative blastema polarity is controlled by Wnt/β-catenin signaling. It is well known that a regeneration blastema of appendages of vertebrates such as fish and amphibians grows distally. However, it remains unclear whether a regeneration blastema in vertebrate appendages can grow proximally. Here, we show that a regeneration blastema in zebrafish fins can grow proximally along the proximodistal axis by calcineurin inhibition. We used fin excavation in adult zebrafish to observe unidirectional regeneration from the anterior cut edge (ACE) to the posterior cut edge (PCE) of the cavity and this unidirectional regeneration polarity occurs as the PCE fails to build blastemas. Furthermore, we found that calcineurin activities in the ACE were greater than in the PCE. Calcineurin inhibition induced PCE blastemas, and calcineurin hyperactivation suppressed fin regeneration. Collectively, these findings identify calcineurin as a molecular switch to specify the PCE blastema of the proximodistal axis and regeneration polarity in zebrafish fin.
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Project description:Understanding how mechanical stimulation affects cellular behaviors during tissue regeneration offers valuable insight into the mechanisms that regulate injury repair. We incorporated a swim tunnel exercise regimen during zebrafish caudal fin regeneration to explore exercise loading impacts on a robust model of tissue regeneration. Early exercise loading, initiated before or during blastema formation, resulted in reduced regenerative outcomes. Long-term tracking of fluorescently labeled cell lineages showed exercise loading disrupted blastemal mesenchyme formation. Transcriptomic profiling and section staining indicated loading reduced an extracellular matrix (ECM) gene expression program, including for hyaluronic acid (HA) synthesis. Like exercise loading, HA synthesis inhibition or blastemal HA depletion disrupted blastema formation. We considered if injury-upregulated HA establishes a pro-regenerative environment facilitating mechanotransduction. HA density across the blastema correlated with nuclear localization of the mechanotransducer Yes-associated protein (Yap). Further, exercise loading or HA depletion decreased nuclear Yap and Proliferative Cell Nuclear Antigen staining. We conclude early loading during fin regeneration disrupts expression of an HA-rich ECM supporting blastema expansion. Our study of mechanical loading during fin regeneration reveals a stage-dependent response similar to that seen in mammalian skeletal repair, where early exercise—applied during blastema establishment—impairs regeneration, while delayed loading during outgrowth does not, suggesting a conserved sensitivity to the timing and intensity of mechanical stimuli in regenerative processes.
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Project description:Regeneration depends on the ability of mature cells at the injury site to respond to injury, generating tissue-specific progenitors that incorporate the blastema and proliferate to reconstitute the original organ architecture. The metabolic microenvironment has been tightly connected to cell function and identity during development and tumorigenesis. Yet, the link between metabolism and cell identity at the mechanistic level in a regenerative context remains unclear. The adult zebrafish caudal fin, and bone cells specifically, have been crucial for the understanding of mature cell contribution to tissue regeneration. Here, we use this model to explore the relevance of glucose metabolism for the cell fate transitions preceding new osteoblast formation and blastema assembly. We show that injury triggers a shift in the metabolic profile at early stages of regeneration, enhancing glycolysis at the expense of mitochondrial oxidation. This metabolic switch mediates transcriptional changes that make mature osteoblast amenable to be reprogramed into pre-osteoblasts and induces cell cycle re-entry and progression. Manipulation of the metabolic profile led to severe reduction of the pre-osteoblast pool, diminishing their capacity to generate new osteoblasts, and to a complete abrogation of blastema formation. Overall, our data indicate that metabolic alterations have a powerful instructive role in regulating genetic programs that dictate fate decisions and stimulate proliferation, thereby providing a deeper understanding on the mechanisms regulating blastema formation and bone regeneration.
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Project description:Comparative studies of vertebrate appendages offer a powerful framework for uncovering shared components of an ancestral regeneration toolkit. Here, we employed a multi-omics comparative approach leveraging the regenerative capacity of the axolotl, zebrafish, and Polypterus senegalus, a fish capable of full fin regeneration. We identified conserved markers of proximal and distal blastema territories, shared activation of DNA damage repair, hif1a-mediated hypoxia response, and sequential activation of pro- and anti-inflammatory program. Apical epithelial ridge markers were expressed in both the wound epidermis and distal mesenchyme during limb and fin regeneration. Notably, hif4a-expressing erythrocytes were uniquely associated with proximal limb and fin amputations but not fin rays, while epidermal myoglobin expression was upregulated only in Polypterus and zebrafish fins. Genome-wide chromatin profiling identified candidate regeneration-responsive elements and a conserved enrichment for AP-1 transcription factor binding. Together, these finding identify shared and derived mechanisms of limb and fin regeneration.
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