Journal
EMBO MOLECULAR MEDICINE
Volume 12, Issue 8, Pages -Publisher
WILEY
DOI: 10.15252/emmm.201911674
Keywords
axon transport; CNSaxon regeneration; optic nerve; p110 delta; phosphoinositide 3-kinase
Categories
Funding
- MRC-Sackler
- International Spinal Research Trust [NRB110]
- Wellcome Trust [095691/Z/11/Z]
- ERA-NET NEURON grant AxonRepair
- European Union
- Operational Programme Research, Development and Education of the 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
- National Eye Research Council
- MRC
- DFG [SFB 958, SFB TRR 186]
- EMBO ALTF [1436-2015]
- MS Society UK
- BBSRC [BBS/E/B/000C0409, BBS/E/B/000C0427]
- Wellcome Trust [095691/Z/11/Z] Funding Source: Wellcome Trust
- BBSRC [BBS/E/B/000C0428, BBS/E/B/000C0427, BBS/E/B/000C0409] Funding Source: UKRI
- MRC [MR/R004463/1, MR/R004544/1, MR/K017047/1, G0300336] Funding Source: UKRI
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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.
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