Canonical mTOR protein supports complete fin regeneration with selective effects on myeloid transcriptional programs

Salamanders possess unique amino acid expansions in mTOR proposed to confer hypersensitive kinase activity, raising the possibility that canonical mTOR is insufficient to support complex appendage regeneration. We tested this hypothesis in the Senegal bichir (Polypterus senegalus), a ray-finned fish capable of complete fin regeneration.

Fin amputation triggered rapid activation of mTOR signaling, and pharmacological inhibition of mTOR abolished regeneration despite successful wound closure. Single-nucleus RNA sequencing across regenerative stages revealed selective upregulation of mTOR pathway components in proliferating epidermal and connective tissue cells, and in myeloid cells. Inhibition of mTOR specifically attenuated the induction of translational machinery and glycolytic profiles and disproportionately affected myeloid transcriptional states associated with innate immune recognition, interferon-associated signaling, and antigen processing.