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PI 3-kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS
- Publication Year :
- 2019
- Publisher :
- Cold Spring Harbor Laboratory, 2019.
-
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: p110 and p110{delta}. Overexpressing p110 in CNS neurons had no effect, however expression of p110{delta} 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 p110. Furthermore, viral delivery of p110{delta} 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 p110{delta} facilitates axon regeneration by functioning in a hyperactive fashion.
- Subjects :
- Genetically modified mouse
0303 health sciences
animal structures
Regeneration (biology)
Central nervous system
Cell
Biology
Cell biology
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
medicine.anatomical_structure
nervous system
chemistry
Peripheral nervous system
embryonic structures
medicine
Phosphatidylinositol
Axon
030217 neurology & neurosurgery
PI3K/AKT/mTOR pathway
030304 developmental biology
Subjects
Details
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....3489aa2318f5f2428a7995198533cf1b