Motoneuron-Specific PTEN Deletion in Mice Induces Neuronal Hypertrophy and Also Regeneration after Facial Nerve Injury

Abstract

In postmitotic neurons, several tumor suppressor genes (TSGs), including p53, Rb, and PTEN, modulate the axon regeneration success after injury. Particularly, PTEN inhibition is a key driver of successful CNS axon regeneration after optic nerve or spinal cord injury. In contrast, in peripheral neurons, TSG influence in neuronal morphology, physiology, and pathology has not been investigated to the same depth. In this study, we conditionally deleted PTEN from mouse facial motoneurons (Chat-Cre/Pten loxP/loxP ) and analyzed neuronal responses in vivo with or without peripheral facial nerve injury in male and female mice. In uninjured motoneurons, PTEN loss induced somatic, axonal, and nerve hypertrophy, synaptic terminal enlargement and reduction in physiological whisker movement. Despite these morphologic and physiological changes, PTEN deletion positively regulated facial nerve regeneration and recovery of whisker movement after nerve injury. Regenerating PTEN-deficient motoneurons upregulated P-CREB and a signaling pathway involving P-Akt, P-PRAS40, P-mTOR, and P-4EBP1. In aged mice (12 months), PTEN deletion induced hair loss and facial hyperplasia of the epidermis. This suggests a time window in younger mice with PTEN loss stimulating axon growth after injury, however, at the risk of hyperplasia formation at later time points in the old animal. Overall, our data highlight a dual TSG function with PTEN loss impairing physiological neuron function but furthermore underscoring the positive effects of PTEN ablation in axon regeneration also for the PNS.

Ubiquitin Proteasome System and Microtubules Are Master Regulators of Central and Peripheral Nervous System Axon Degeneration

“…In agreement with the role of E3 ligase in maintaining and promoting axonal survival, the UPS related neural precursor cell expressed developmentally down-regulated protein 4 (Nedd4) induces the degradation of PTEN and promotes axon branching and regeneration [91]. The crucial role of PTEN in blocking axonal regeneration has been confirmed in a very recent paper showing that PTEN deletion induces neuron hypertrophy and regeneration [92]. Nedd4 is also a critical regulator of excitability of nociceptive neurons [93]; thus, it has the potentiality to induce both axon regeneration and pain relief.…”

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SRF deletion results in earlier disease onset in a mouse model of amyotrophic lateral sclerosis

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