PI 3-kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS

Nieuwenhuis, Bart, Barber, Amanda C., Evans, Rachel S., Pearson, Craig S., Fuchs, Joachim, MacQueen, Amy R., van Erp, Susan, Haenzi, Barbara, Hulshof, Lianne A., Osborne, Andrew, Conceicao, Raquel, Khatib, Tasneem Z., Deshpande, Sarita S., Cave, Joshua, ffrench-Constant, Charles ORCID: https://orcid.org/0000-0002-5621-3377, Smith, Patrice D., Okkenhaug, Klaus, Eickholt, Britta J., Martin, Keith R., Fawcett, James W. and Eva, Richard (2020) PI 3-kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS. EMBO Molecular Medicine, 12 (8). ISSN 1757-4676

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Abstract

Peripheral nervous system (PNS) neurons support axon regeneration into adulthood, whereas central nervous system (CNS) neurons lose regenerative ability after development. To better understand this decline whilst aiming to improve regeneration, we focused on phosphoinositide 3-kinase (PI3K) and its product phosphatidylinositol (3,4,5)-trisphosphate (PIP3). We demonstrate that adult PNS neurons utilise two catalytic subunits of PI3K for axon regeneration: p110α and p110δ. However, in the CNS, axonal PIP3 decreases with development at the time when axon transport declines and regenerative competence is lost. Overexpressing p110α in CNS neurons had no effect; however, expression of p110δ restored axonal PIP3 and increased regenerative axon transport. p110δ expression enhanced CNS regeneration in both rat and human neurons and in transgenic mice, functioning in the same way as the hyperactivating H1047R mutation of p110α. Furthermore, viral delivery of p110δ promoted robust regeneration after optic nerve injury. These findings establish a deficit of axonal PIP3 as a key reason for intrinsic regeneration failure and demonstrate that native p110δ facilitates axon regeneration by functioning in a hyperactive fashion.

Item Type: Article
Additional Information: Funding Information: KO received consultancy payments and/or research funding from Karus Therapeutics, Gilead Sciences and GlaxoSmithKline. Funding Information: We acknowledge the Babraham Gene Targeting Facilities for the generation of the Rosa26 p110 mouse strains and would like to thank Dr. Len Stephens and Dr. Phill Hawkins (Babraham) for the gift of the GFP-AKT-PH mouse strain, and for their advice and support. RE, JWF, KRM, ACB, BN, RSE and CSP were supported by grants from MRC-Sackler, International Spinal Research Trust (NRB110), Wellcome Trust, ERA-NET NEURON grant AxonRepair, the European Union, the Operational Programme Research, Development and Education in the framework of the project ?Centre of Reconstructive Neuroscience?, Czech Ministry of Education, CZ.02.1.01/0.0./0.0/15_003/0000419, Medical Research Council MRC (MR/R004544/1, MR/R004463/1), Christopher and Dana Reeve Foundation, Cambridge Eye Trust, Fight for Sight, and National Eye Research Council and a core support grant from the Wellcome Trust and MRC to the Wellcome Trust?Medical Research Council Cambridge Stem Cell Institute. BJE funding was provided by the DFG (SFB 958, TP16; SFB TRR 186, TP10). SvE was funded by EMBO ALTF 1436-2015, and SvE and Cff-C by MS Society UK. KO laboratory funding was provided by the BBSRC (BBS/E/B/000C0409, BBS/E/B/000C0427) and the Wellcome Trust (095691/Z/11/Z). Funding Information: We acknowledge the Babraham Gene Targeting Facilities for the generation of the Rosa26 p110 mouse strains and would like to thank Dr. Len Stephens and Dr. Phill Hawkins (Babraham) for the gift of the GFP‐AKT‐PH mouse strain, and for their advice and support. RE, JWF, KRM, ACB, BN, RSE and CSP were supported by grants from MRC‐Sackler, International Spinal Research Trust (NRB110), Wellcome Trust, ERA‐NET NEURON grant AxonRepair, the European Union, the Operational Programme Research, Development and Education in the framework of the project “Centre of Reconstructive Neuroscience”, Czech Ministry of Education, CZ.02.1.01/0.0./0.0/15_003/0000419, Medical Research Council MRC (MR/R004544/1, MR/R004463/1), Christopher and Dana Reeve Foundation, Cambridge Eye Trust, Fight for Sight, and National Eye Research Council and a core support grant from the Wellcome Trust and MRC to the Wellcome Trust—Medical Research Council Cambridge Stem Cell Institute. BJE funding was provided by the DFG (SFB 958, TP16; SFB TRR 186, TP10). SvE was funded by EMBO ALTF 1436‐2015, and SvE and Cff‐C by MS Society UK. KO laboratory funding was provided by the BBSRC (BBS/E/B/000C0409, BBS/E/B/000C0427) and the Wellcome Trust (095691/Z/11/Z).
Uncontrolled Keywords: axon transport,cns axon regeneration,optic nerve,p110 delta,phosphoinositide 3-kinase,molecular medicine ,/dk/atira/pure/subjectarea/asjc/1300/1313
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: LivePure Connector
Date Deposited: 18 Jul 2022 11:30
Last Modified: 12 Aug 2022 05:36
URI: https://ueaeprints.uea.ac.uk/id/eprint/86450
DOI: 10.15252/emmm.201911674

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