Peripheral regeneration of Aβ low‐threshold mechanoreceptors is limited despite activation of regenerative transcriptional pathways

Peripheral neurons can regenerate after nerve injury, yet functional recovery is often incomplete due to non-specific or incomplete target reinnervation. Among sensory neuron subtypes, Aβ low-threshold mechanoreceptors (Aβ-LTMRs) mediate discriminative touch, a modality often incompletely restored after nerve injury. However, the mechanisms governing Aβ-LTMR regeneration remain largely unexplored. Here, we characterised the anatomical and transcriptional features of Aβ-LTMR regeneration after nerve injury. We assessed the extent of axonal regeneration after sciatic nerve crush and the preferential regeneration following femoral nerve transection using Calb1-Cre/tdTomato reporter mice. In both models, regeneration was incomplete, failing to reach control values. Moreover, Aβ-LTMRs showed a modest but significant preferential regeneration to cutaneous rather than muscle pathways. To define the molecular programme underlying this response, we performed ribosome-bound RNA sequencing from Calb1-Cre/Ribotag mice 7 days after nerve crush. Aβ-LTMRs upregulated canonical regeneration-associated genes, including Atf3, Sprr1a, Gal, and Gap43. Comparison with published RNA-seq datasets from other sensory neuron populations revealed only modest overlap, indicating that the core injury response shared between neurons is accompanied by a neuron subtype-specific programme. Together, these findings define the regenerative profile of Aβ-LTMRs across anatomical and transcriptomic levels, revealing the limited regenerative capacity of this neuron subpopulation despite robust activation of classical regeneration-associated genes. KEY POINTS: Peripheral neurons can regenerate after nerve injury, but functional recovery is often incomplete due to limited axonal regrowth and inaccurate target reinnervation. Aβ low-threshold mechanoreceptors (Aβ-LTMRs) mediate discriminative touch, a sensory modality that is frequently not fully restored following nerve injury. In this study, we investigated the regenerative capacity of Aβ-LTMRs using complementary anatomical and transcriptomic approaches. We show that Aβ-LTMRs exhibit limited regeneration after nerve injury, despite activating canonical regeneration-associated transcriptional programs. The results help us better understand how regenerative capacity differs between neuronal subtypes and highlight the importance of defining subtype-specific regenerative responses to improve axonal growth and promote accurate target reinnervation.