Subtype-Specific Regeneration of Retinal Ganglion Cells following Axotomy: Effects of Osteopontin and mTOR Signaling

Abstract

SUMMARY In mammals, few retinal ganglion cells (RGCs) survive following axotomy and even fewer regenerate axons. This could reflect differential extrinsic influences or the existence of subpopulations that vary in their responses to injury. We tested these alternatives by comparing responses of molecularly distinct subsets of mouse RGCs to axotomy. Survival rates varied dramatically among subtypes, with alpha-RGCs (αRGCs) surviving preferentially. Among survivors, αRGCs accounted for nearly all regeneration following down-regulation of PTEN, which activates the mTOR pathway. αRGCs have uniquely high mTOR signaling levels among RGCs and also selectively express osteopontin (OPN) and receptors for the growth factor, insulin-like growth factor 1 (IGF-1). Administration of OPN plus IGF-1 promotes regeneration as effectively as down-regulation of PTEN; however, regeneration is still confined to αRGCs. Our results reveal dramatic subtype-specific differences in the ability of RGCs to survive and regenerate following injury, and they identify promising agents for promoting axonal regeneration.

Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration

“…Optic nerve injury leads to numerous pathological changes in RGCs and reversing some of these changes improves cell survival, although these effects are often transitory and for the most part promote little or no axon regeneration (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). Regeneration per se can be induced by intraocular inflammation combined with elevated cAMP (11,12), counteracting cell-intrinsic (13)(14)(15) or cellextrinsic (16,17) suppressors of axon growth, oncomodulin and other growth factors (18)(19)(20)(21)(22), or elevated physiological activity (23,24). Some of these treatments act synergistically and enable a modest number of RGCs to reestablish connections with appropriate target areas in the brain (25)(26)(27).…”

“…6), indicate that Zn 2+ plays an early and critical role in regulating RGC death. In terms of cell-type specificity, pten deletion selectively enhances the survival of RGCs with high basal mammalian target of rapamycin (mTOR) activity (20), but only transiently (Fig. 6).…”

“…pten deletion de-represses PI3 kinase-Akt signaling (13) and promotes regeneration for only αRGCs (20). Combining Zn 2+ chelation with pten deletion enabled some axons to regenerate the full length of the optic nerve in just 2 wk, and by 12 wk many axons had crossed the optic chiasm.…”

Promoting axon regeneration in the adult CNS by modulation of the melanopsin/GPCR signaling

“…When presented with permissive substrates such as a sciatic nerve graft, only axons of small populations of retinal ganglion cells (RGCs) regrow into the graft (7). When the intrinsic growth program is boosted, distinct subtypes of RGCs regenerate their axons (8). These findings indicate that the differential responses of RGCs to axotomy and growth stimulation are related to their intrinsic properties.…”

Advances in peripheral nerve regeneration as it relates to VCA

“…PTEN inhibits protein translation by repressing PI3 kinase activation and downstream signaling. Deletion of PTEN was found to enhance axonal regeneration and allow reactivation of PI3 kinase pathway, as demonstrated by Dun et al 87,88 Interestingly, co-deletion of PTEN and SOCS3 led to sustained axonal regeneration ability by retinal ganglionic cells. 89 The same results were found to be true in corticospinal neurons as well.…”