PI3-kinase delta enhances axonalPIP3to support axon regeneration in the adultCNS

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 adultPNSneurons utilise two catalytic subunits ofPI3K for axon regeneration: p110 alpha and p110 delta. However, in theCNS, axonalPIP(3)decreases with development at the time when axon transport declines and regenerative competence is lost. Overexpressing p110 alpha inCNSneurons had no effect; however, expression of p110 delta restored axonalPIP(3)and increased regenerative axon transport. p110 delta expression enhancedCNSregeneration in both rat and human neurons and in transgenic mice, functioning in the same way as the hyperactivating H1047R mutation of p110 alpha. Furthermore, viral delivery of p110 delta promoted robust regeneration after optic nerve injury. These findings establish a deficit of axonalPIP(3)as a key reason for intrinsic regeneration failure and demonstrate that native p110 delta facilitates axon regeneration by functioning in a hyperactive fashion.