Regeneration Rewritten: Translational Control as a Driver of Tissue Repair

One of the most profound mysteries in biology is why some organisms, such as the axolotl, can regenerate entire limbs, while mammals cannot. For decades, efforts to understand regeneration have focused largely on transcription—the process by which genes are turned on or off. However, this perspective overlooks a critical layer of gene regulation: translation, the step where proteins are actually produced.

In this work, we uncover a fundamentally new principle: rapid, selective activation of protein synthesis is a defining feature of regenerative capacity. Rather than waiting for new genes to be transcribed, regenerative tissues mobilize a pre-existing pool of mRNAs and rapidly translate them into proteins immediately after injury. This “on-demand” translational response provides a powerful and previously underappreciated mechanism for initiating tissue repair.

Using polysome profiling and sequencing approaches, we demonstrate that within hours of limb amputation in the axolotl, there is a dramatic, tissue-wide increase in protein synthesis. This response occurs before cell proliferation begins, indicating that translation is not simply a consequence of regeneration—it is an early and instructive event. In striking contrast, non-regenerative injuries in mice fail to activate this global translational response, revealing a key molecular distinction between regenerative and non-regenerative systems .

A Hidden Layer of Gene Regulation: Translating the “Dormant” Transcriptome

A central discovery of this study is that regeneration relies heavily on selective translation of pre-existing mRNAs, rather than changes in transcription. We identified hundreds of transcripts that are not upregulated at the RNA level but are instead recruited to ribosomes and efficiently translated following injury.

This finding challenges the long-standing assumption that transcriptional changes dominate early regenerative responses. Instead, we reveal that the cell maintains a “dormant transcriptome”—a reservoir of mRNAs poised for rapid activation when needed. Upon injury, these transcripts are selectively engaged to produce proteins essential for wound healing.

Notably, many of these translationally activated mRNAs encode:

• Components of the protein synthesis machinery itself (ribosomal proteins and initiation factors)

• Regulators of redox balance, including antioxidants that control reactive oxygen species (ROS)

• Factors involved in cellular stress responses and tissue remodeling

This suggests a coordinated program in which cells rapidly amplify their translational capacity while simultaneously managing oxidative stress—two processes critical for successful regeneration.

mTOR as a Master Regulator of Regenerative Translation

We next identify the mTORC1 signaling pathway as a central regulator of this translational response. mTOR is a conserved kinase that integrates environmental cues such as nutrients, energy status, and stress to control protein synthesis.

In the axolotl, limb amputation triggers robust activation of mTORC1, leading to phosphorylation of key translational regulators and a global increase in protein production. Pharmacological inhibition of mTOR blocks this response, resulting in:

• Impaired wound closure

• Defective epithelial migration

• Disrupted control of reactive oxygen species

• Failure to properly initiate regeneration

These findings establish that mTOR-dependent translation is not merely supportive—but essential—for regeneration .

Importantly, inhibiting translation downstream of mTOR recapitulates these defects, demonstrating that the regenerative role of mTOR is largely mediated through its control of protein synthesis.

Evolution Shapes Regeneration: A Hypersensitive mTOR

A major conceptual advance from this work is the discovery that the regenerative capacity of the axolotl is linked to evolutionary adaptations in the mTOR protein itself.

We identify unique sequence insertions in axolotl mTOR that are absent in mammals. These changes fundamentally alter the behavior of the kinase, creating a “hypersensitive” mTOR that:

• Is primed for activation at baseline

• Responds rapidly to small changes in nutrient availability

• Maintains a broader dynamic range of signaling

By engineering these axolotl-specific features into human cells, we demonstrate that they are sufficient to confer increased sensitivity to nutrient signals and enhanced translational responsiveness.

This suggests that evolution has tuned a core metabolic signaling pathway to enable regeneration, effectively rewiring how cells interpret environmental cues after injury.

Linking Metabolism, Translation, and Regeneration

Our findings also uncover a critical role for nutrient sensing in regeneration. Amino acid transporters are upregulated after injury, and blocking amino acid uptake prevents both mTOR activation and wound healing.

This reveals a direct connection between:

• Metabolic inputs (nutrients)

• Signaling pathways (mTOR)

• Gene expression outputs (translation)

Together, these processes form an integrated system that allows regenerative organisms to rapidly convert environmental signals into functional protein production.

A New Framework for Regenerative Biology

This study establishes a new paradigm for understanding tissue regeneration:

Regeneration is driven not only by what genes are expressed, but by how—and how quickly—they are translated.

Rather than relying on slow transcriptional programs, regenerative systems deploy a rapid, translationally controlled response that enables immediate adaptation to injury. This mechanism provides speed, precision, and flexibility—key features required for successful tissue repair.

Implications for Human Health and Disease

These findings have broad implications for regenerative medicine and disease:

• They suggest that enhancing translational control pathways may improve wound healing and tissue repair in humans

• They identify mTOR as a potential target for modulating regenerative capacity without inducing uncontrolled growth

• They raise the possibility that engineering “regeneration-like” signaling states could overcome intrinsic limitations in mammalian tissues

Ultimately, this work provides a foundation for rethinking therapeutic strategies—not by changing which genes are present, but by controlling when and how they are translated.

Zhulyn O, Rosenblatt HD, Shokat L, Dai S, Kuzuoglu-Öztürk D, Zhang Z, Ruggero D, Shokat KM, Barna M. Evolutionarily divergent mTOR remodels translatome for tissue regeneration. Nature. 2023 Aug;620(7972):163-171. doi: 10.1038/s41586-023-06365-1. Epub 2023 Jul 26. PMID: 37495694; PMCID: PMC11181899.