GSK3-CRMP2 signaling mediates axonal regeneration induced by Pten knockout.
Marco LeibingerAlexander M HillaAnastasia AndreadakiDietmar FischerPublished in: Communications biology (2019)
Knockout of phosphatase and tensin homolog (PTEN-/-) is neuroprotective and promotes axon regeneration in mature neurons. Elevation of mTOR activity in injured neurons has been proposed as the primary underlying mechanism. Here we demonstrate that PTEN-/- also abrogates the inhibitory activity of GSK3 on collapsin response mediator protein 2 (CRMP2) in retinal ganglion cell (RGC) axons. Moreover, maintenance of GSK3 activity in Gsk3 S/A knockin mice significantly compromised PTEN-/--mediated optic nerve regeneration as well as the activity of CRMP2, and to a lesser extent, mTOR. These GSK3S/A mediated negative effects on regeneration were rescued by viral expression of constitutively active CRMP2T/A, despite decreased mTOR activation. Gsk3 S/A knockin or CRMP2 inhibition also decreased PTEN-/- mediated neurite growth of RGCs in culture and disinhibition towards CNS myelin. Thus, the GSK3/CRMP2 pathway is essential for PTEN-/- mediated axon regeneration. These new mechanistic insights may help to find novel strategies to promote axon regeneration.
Keyphrases
- pi k akt
- cell proliferation
- signaling pathway
- stem cells
- optic nerve
- spinal cord
- poor prognosis
- spinal cord injury
- type diabetes
- cell therapy
- sars cov
- single cell
- adipose tissue
- optical coherence tomography
- multiple sclerosis
- bone marrow
- binding protein
- skeletal muscle
- blood brain barrier
- metabolic syndrome
- insulin resistance
- amino acid
- white matter