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

Bart Nieuwenhuis, Amanda C. Barber, Rachel S. Evans, Craig S. Pearson, Joachim Fuchs, Amy R. MacQueen, Susan van Erp, Barbara Haenzi, Lianne A. Hulshof, Andrew Osborne, Raquel Conceicao, Tasneem Z. Khatib, Sarita S. Deshpande, Joshua Cave, Charles ffrench-Constant, Patrice D. Smith, Klaus Okkenhaug, Britta J. Eickholt, Keith R. Martin, James W. FawcettRichard Eva

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)
4 Downloads (Pure)


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.

Original languageEnglish
Article numbere11674
JournalEMBO Molecular Medicine
Issue number8
Early online date17 Jun 2020
Publication statusPublished - 7 Aug 2020


  • axon transport
  • CNS axon regeneration
  • optic nerve
  • p110 delta
  • phosphoinositide 3-kinase

Cite this