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bioRxiv · 10.1101/2025.06.04.657750

UNWANTED AXON GROWTH: PTEN AND THE SUPPRESSION OF AXON PLASTICITY IN ADULT NERVES

Eaton, S.·Komirishetty, P.·Larouche, M.·Areti, A.·Ong, H.·Martinez, J.·Zochodne, D. W.
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Abstract

In adults, peripheral nerves comprise bundles of disseminated motor, sensory and autonomic axons that are considered stable neuroanatomical units. The only exceptions to this established wiring are very distal terminal branches in target organs, such as skin. Here we provide a remarkable deviation from this state of affairs in the peripheral nerves of mice with a conditional knockout of sensory neuron PTEN (phosphatase and tensin homolog deleted on chromosome ten). PTEN is normally expressed in adult sensory neurons, particularly small IB4 nonpeptidergic subtypes and its knockdown after injury or during experimental diabetes improves axon regrowth. We studied Advillin Cre;PTEN null mice lacking PTEN in their sensory neurons. As might be expected, their harvested and cultured DRG neurons displayed enhanced neurite outgrowth in vitro. In vivo, these mice were healthy and had a normal sensory behavioural phenotype. However, the nerves of mice lacking sensory neuron PTEN were highly abnormal, with augmented clusters of small myelinated and unmyelinated axons populating endoneurial fascicles of their peripheral nerve trunks. The axon clusters did not disrupt normal fascicular anatomy but invested the epidermis with greater axon numbers. Within endoneurial fascicles, supernumerary axons formed regenerative units and expressed ongoing growth markers, unlike normal adult axons. This was not accompanied by rises in dorsal root ganglia (DRG) neuron numbers, indicating enhanced distal sprouting from parent neurons. Additionally, sprouting axons were electrophysiologically intact, generating rises in the amplitudes of sensory nerve action potentials. Despite this extensive regenerative activity of intact nerves, regeneration indices after superimposed injury were only modestly enhanced or unchanged. This unusual behaviour of adult sensory axons lacking a single growth-suppressive molecule may identify insights into what molecular constraints the nervous system normally utilizes to suppress inappropriate plasticity.

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Eaton, S., Komirishetty, P., Larouche, M., Areti, A., Ong, H., Martinez, J., Zochodne, D. W.. 2025-06-08. UNWANTED AXON GROWTH: PTEN AND THE SUPPRESSION OF AXON PLASTICITY IN ADULT NERVES. https://doi.org/10.1101/2025.06.04.657750

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