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

Abstract The mechanistic target of rapamycin (mTOR) is a conserved regulator of cellular growth, metabolism, and tissue repair. 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. We propose that salamander-specific mTOR hypersensitivity represents an evolutionary acceleration of an ancestral regenerative program, rather than a prerequisite for limb regeneration.