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

Amanda C Barber, Rachel S Evans, Bart Nieuwenhuis, Craig S Pearson, Joachim Fuchs, Amy R MacQueen, Susan van Erp, Barabara Haenzi, Lianne A Hulshof, Andrew Osborne, Raquel Conceicao, Sarita S Deshpande, Joshua Cave, Charles ffrench-Constant, Patrice D Smith, Klaus Okkenhaug, Britta J Eickholt, Keith R Martin, James W Fawcett, View ORCID ProfileRichard Eva
doi: https://doi.org/10.1101/787994
Amanda C Barber
University of Cambridge;
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Rachel S Evans
Universityof Cambridge;
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Bart Nieuwenhuis
University of Cambridge;
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Craig S Pearson
University of Cambridge;
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Joachim Fuchs
Charite - Universitatsmedizin Berlin;
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Amy R MacQueen
Babraham Institute;
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Susan van Erp
University of Edinburgh;
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Barabara Haenzi
University of Cambridge;
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Lianne A Hulshof
University of Cambridge;
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Andrew Osborne
University of Cambridge;
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Raquel Conceicao
University of Cambridge;
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Sarita S Deshpande
University of Cambridge;
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Joshua Cave
University of Cambridge;
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Charles ffrench-Constant
Uiniversity of Edinburgh;
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Patrice D Smith
Carleton University;
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Klaus Okkenhaug
University of Cambridge;
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Britta J Eickholt
Charite - Universitatsmedizin Berlin;
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Keith R Martin
University of Cambridge, Centre for Eye Research Australia and University of Melbourne;
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James W Fawcett
University of Cambridge and Czech Academy of Sciences
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Richard Eva
University of Cambridge;
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  • ORCID record for Richard Eva
  • For correspondence: re263@cam.ac.uk
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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 found that neuronal PIP3 decreases with maturity in line with regenerative competence, firstly in the cell body and subsequently in the axon. We show that adult PNS neurons utilise two catalytic subunits of PI3K for efficient regeneration: p110α and p110δ. Overexpressing p110α in CNS neurons had no effect, however expression of p110δ restored axonal PIP3 and enhanced CNS regeneration in 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 demonstrate a deficit of axonal PIP3 as a reason for intrinsic regeneration failure and show that native p110δ facilitates axon regeneration by functioning in a hyperactive fashion.

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Posted November 04, 2019.
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PI 3-kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS
Amanda C Barber, Rachel S Evans, Bart Nieuwenhuis, Craig S Pearson, Joachim Fuchs, Amy R MacQueen, Susan van Erp, Barabara Haenzi, Lianne A Hulshof, Andrew Osborne, Raquel Conceicao, Sarita S Deshpande, Joshua Cave, Charles ffrench-Constant, Patrice D Smith, Klaus Okkenhaug, Britta J Eickholt, Keith R Martin, James W Fawcett, Richard Eva
bioRxiv 787994; doi: https://doi.org/10.1101/787994
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PI 3-kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS
Amanda C Barber, Rachel S Evans, Bart Nieuwenhuis, Craig S Pearson, Joachim Fuchs, Amy R MacQueen, Susan van Erp, Barabara Haenzi, Lianne A Hulshof, Andrew Osborne, Raquel Conceicao, Sarita S Deshpande, Joshua Cave, Charles ffrench-Constant, Patrice D Smith, Klaus Okkenhaug, Britta J Eickholt, Keith R Martin, James W Fawcett, Richard Eva
bioRxiv 787994; doi: https://doi.org/10.1101/787994

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