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000163734 037__ $$aDZNE-2022-00473
000163734 041__ $$aEnglish
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000163734 1001_ $$00000-0001-6978-1915$$aMeyer Zu Reckendorf, Sofia$$b0
000163734 245__ $$aMotoneuron-Specific PTEN Deletion in Mice Induces Neuronal Hypertrophy and Also Regeneration after Facial Nerve Injury.
000163734 260__ $$aWashington, DC$$bSoc.$$c2022
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000163734 520__ $$aIn 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 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.SIGNIFICANCE STATEMENT Tumor 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.
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000163734 650_7 $$2Other$$aAkt
000163734 650_7 $$2Other$$aCREB
000163734 650_7 $$2Other$$aPTEN
000163734 650_7 $$2Other$$afacial nerve
000163734 650_7 $$2Other$$amotoneuron
000163734 650_7 $$2Other$$anerve regeneration
000163734 650_2 $$2MeSH$$aAnimals
000163734 650_2 $$2MeSH$$aAxons: physiology
000163734 650_2 $$2MeSH$$aFacial Nerve Injuries: genetics
000163734 650_2 $$2MeSH$$aFacial Nerve Injuries: pathology
000163734 650_2 $$2MeSH$$aFemale
000163734 650_2 $$2MeSH$$aHyperplasia: pathology
000163734 650_2 $$2MeSH$$aHypertrophy: pathology
000163734 650_2 $$2MeSH$$aMale
000163734 650_2 $$2MeSH$$aMice
000163734 650_2 $$2MeSH$$aMotor Neurons: metabolism
000163734 650_2 $$2MeSH$$aNerve Regeneration: genetics
000163734 650_2 $$2MeSH$$aPTEN Phosphohydrolase: metabolism
000163734 650_2 $$2MeSH$$aTumor Suppressor Protein p53
000163734 7001_ $$aMoser, Diana$$b1
000163734 7001_ $$aBlechschmidt, Anna$$b2
000163734 7001_ $$aJoga, Venkata Neeha$$b3
000163734 7001_ $$aSinske, Daniela$$b4
000163734 7001_ $$aHegler, Jutta$$b5
000163734 7001_ $$aDeininger, Stefanie$$b6
000163734 7001_ $$0P:(DE-2719)9001873$$aCastanese, Alberto$$b7$$udzne
000163734 7001_ $$aVettorazzi, Sabine$$b8
000163734 7001_ $$aAntoniadis, Gregor$$b9
000163734 7001_ $$0P:(DE-2719)2812855$$aBöckers, Tobias$$b10$$udzne
000163734 7001_ $$00000-0001-7685-3796$$aKnöll, Bernd$$b11
000163734 77318 $$2Crossref$$3journal-article$$a10.1523/jneurosci.1305-21.2022$$bSociety for Neuroscience$$d2022-02-11$$n12$$p2474-2491$$tThe Journal of Neuroscience$$v42$$x0270-6474$$y2022
000163734 773__ $$0PERI:(DE-600)1475274-8$$a10.1523/JNEUROSCI.1305-21.2022$$gVol. 42, no. 12, p. 2474 - 2491$$n12$$p2474-2491$$tThe journal of neuroscience$$v42$$x0270-6474$$y2022
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