Abstract
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 Gsk3S/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. Gsk3S/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.
Highlights
Knockout of phosphatase and tensin homolog (PTEN−/−) is neuroprotective and promotes axon regeneration in mature neurons
PTEN−/− alone induced much stronger pGSK3α- and pGSK3β-levels in retinal ganglion cell (RGC) compared with axotomy in PTEN+/+ mice, while PTEN−/− +Optic nerve crush (ONC) showed no additive effect (Fig. 1b, c)
AKT phosphorylation was induced markedly stronger by PTEN−/− compared with ONC alone (Fig. 1d, i) and neither AKT nor glycogen synthase kinase 3 (GSK3) phosphorylation was further increased after additional ONC (Fig. 1d–f, i, Supplementary Fig. 1b, c, f), thereby verifying our immunohistochemical data
Summary
Knockout of phosphatase and tensin homolog (PTEN−/−) is neuroprotective and promotes axon regeneration in mature neurons. Regarding Pten knockout (PTEN−/−)mediated axon regeneration, the PI3K/AKT/TSC signaling pathway, which activates the mammalian target of rapamycin (mTOR) has been made accountable for the strong neuroprotective as well as axon regeneration promoting effects. These reports suggest that the regenerative effects of PTEN−/− do not solely depend on mTOR, and other downstream effectors of AKT Another approach to promote optic nerve regeneration is the stimulation of RGCs by cytokines of the interleukin 6 (IL-6) superfamily, which are released from activated retinal glial cells after an inflammatory stimulation (IS) induced by lens injury[20,21]. PTEN−/− mediated optic nerve regeneration was significantly reduced by inhibitory CRMP2 phosphorylation in Gsk3S/A knockin mice, but rescued by viral expression of constitutively active CRMP2T/A, indicating its essential role in this context. As the number of publications using PTEN depletion mediated neuronal regeneration is still increasing[28], these mechanistic findings are highly relevant for data interpretation and may facilitate new regenerative strategies mitigating the high cancerogenic risk of PTEN−/− or inhibition in the future
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