Motoneuron-Specific PTEN Deletion in Mice Induces Neuronal Hypertrophy and Also Regeneration after Facial Nerve Injury
| Autor: | Sofia Meyer zu Reckendorf, Diana Moser, Anna Blechschmidt, Venkata Neeha Joga, Daniela Sinske, Jutta Hegler, Stefanie Deininger, Alberto Catanese, Sabine Vettorazzi, Gregor Antoniadis, Tobias Boeckers, Bernd Knöll |
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| Rok vydání: | 2022 |
| Předmět: |
genetics [Facial Nerve Injuries]
Male PTEN metabolism [PTEN Phosphohydrolase] Mice genetics [Nerve Regeneration] Animals ddc:610 nerve regeneration motoneuron Research Articles Facial Nerve Injuries Motor Neurons physiology [Axons] Hyperplasia pathology [Hyperplasia] CREB Akt General Neuroscience pathology [Facial Nerve Injuries] PTEN Phosphohydrolase Hypertrophy metabolism [Motor Neurons] pathology [Hypertrophy] Axons Nerve Regeneration Female facial nerve Tumor Suppressor Protein p53 |
| Zdroj: | The journal of neuroscience 42(12), 2474-2491 (2022). doi:10.1523/JNEUROSCI.1305-21.2022 J Neurosci |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.1305-21.2022 |
| Popis: | 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/PtenloxP/loxP) and analyzed neuronal responsesin vivowith 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.SIGNIFICANCE STATEMENTTumor suppressor genes (TSGs) restrict cell proliferation and growth. TSG inhibition, including p53 and PTEN, stimulates axon regeneration after CNS injury. In contrast, in PNS axon regeneration, TSGs have not been analyzed in great depth. Herein we show enhanced peripheral axon regeneration after PTEN deletion from facial motoneurons. This invokes a signaling cascade with novel PTEN partners, including CREB and PRAS40. In adult mice, PTEN loss induces hyperplasia of the skin epidermis, suggesting detrimental consequences when reaching adulthood in contrast to a beneficial TSG role for regeneration in young adult mice. Thus, our data highlight the double-edged sword nature of interfering with TSG function. |
| Databáze: | OpenAIRE |
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