Sustained axon regeneration induced by co-deletion of PTEN and SOCS3. Nature

F.M. Kirby Neurobiology Center, Children's Hospital, Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
Nature (Impact Factor: 41.46). 11/2011; 480(7377):372-5. DOI: 10.1038/nature10594
Source: PubMed


A formidable challenge in neural repair in the adult central nervous system (CNS) is the long distances that regenerating axons often need to travel in order to reconnect with their targets. Thus, a sustained capacity for axon regeneration is critical for achieving functional restoration. Although deletion of either phosphatase and tensin homologue (PTEN), a negative regulator of mammalian target of rapamycin (mTOR), or suppressor of cytokine signalling 3 (SOCS3), a negative regulator of Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, in adult retinal ganglion cells (RGCs) individually promoted significant optic nerve regeneration, such regrowth tapered off around 2 weeks after the crush injury. Here we show that, remarkably, simultaneous deletion of both PTEN and SOCS3 enables robust and sustained axon regeneration. We further show that PTEN and SOCS3 regulate two independent pathways that act synergistically to promote enhanced axon regeneration. Gene expression analyses suggest that double deletion not only results in the induction of many growth-related genes, but also allows RGCs to maintain the expression of a repertoire of genes at the physiological level after injury. Our results reveal concurrent activation of mTOR and STAT3 pathways as key for sustaining long-distance axon regeneration in adult CNS, a crucial step towards functional recovery.

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Available from: Kevin K Park, Oct 10, 2015
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    • "The yield of RGC is enhanced by transfection of the stem cells with genes regulating RGC development, namely math5 and sox4(Jiang et al., 2013). Similar to ESC/iPSC-derived photoreceptors integrating into the ONL, transplanted adult rat RGC integrate and survive in the ganglion cell layer(Hertz et al., 2014) but, unlike photoreceptors, the long distances over which RGC axons must regenerate to re-innervate central targets is unachievable(Sun et al., 2011). "
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    ABSTRACT: Stem cell therapies are being explored extensively as treatments for degenerative eye disease, either for replacing lost neurons, restoring neural circuits or, based on more recent evidence, as paracrine-mediated therapies in which stem cell-derived trophic factors protect compromised endogenous retinal neurons from death and induce the growth of new connections. Retinal progenitor phenotypes induced from embryonic stem cells/induced pluripotent stem cells (ESCs/iPSCs) and endogenous retinal stem cells may replace lost photoreceptors and retinal pigment epithelial (RPE) cells and restore vision in the diseased eye, whereas treatment of injured retinal ganglion cells (RGCs) has so far been reliant on mesenchymal stem cells (MSC). Here, we review the properties of non-retinal-derived adult stem cells, in particular neural stem cells (NSCs), MSC derived from bone marrow (BMSC), adipose tissues (ADSC) and dental pulp (DPSC), together with ESC/iPSC and discuss and compare their potential advantages as therapies designed to provide trophic support, repair and replacement of retinal neurons, RPE and glia in degenerative retinal diseases. We conclude that ESCs/iPSCs have the potential to replace lost retinal cells, whereas MSC may be a useful source of paracrine factors that protect RGC and stimulate regeneration of their axons in the optic nerve in degenerate eye disease. NSC may have potential as both a source of replacement cells and also as mediators of paracrine treatment. Copyright © 2015. Published by Elsevier B.V.
    Stem Cell Research 02/2015; 2(3). DOI:10.1016/j.scr.2015.02.003 · 3.69 Impact Factor
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    • "In postnatal stage, neurons may be capable of compensating for the loss of mTOR by triggering multiple signaling pathways relevant to axonal growth, and in promoting axonal sprouting. Both mTORdependent and -independent mechanisms of axon regeneration have been demonstrated in previous studies (Christie et al., 2010) where regeneration induced by cytokines relied on JAK/STAT3 but not on mTOR pathway (Sun et al., 2011). Therefore, mTOR, STAT3, and other signaling pathways relevant to axonal growth may be highly active in immature neurons, but not in the adult neurons (Lang et al., 2013) and facilitate sprouting. "
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    ABSTRACT: Mammalian target of rapamycin (mTOR) functions as a master sensor of nutrients and energy, and controls protein translation and cell growth. Deletion of phosphatase and tensin homolog (PTEN) in adult CNS neurons promotes regeneration of injured axons in an mTOR-dependent manner. However, others have demonstrated mTOR-independent axon regeneration in different cell types, raising the question of how broadly mTOR regulates axonal regrowth across different systems. Here we define the role of mTOR in promoting collateral sprouting of spared axons, a key axonal remodeling mechanism by which functions are recovered after CNS injury. Using pharmacological inhibition, we demonstrate that mTOR is dispensable for the robust spontaneous sprouting of corticospinal tract axons seen after pyramidotomy in postnatal mice. In contrast, moderate spontaneous axonal sprouting and induced-sprouting seen under different conditions in young adult mice (i.e., PTEN deletion or degradation of chondroitin proteoglycans; CSPGs) are both reduced upon mTOR inhibition. In addition, to further determine the potency of mTOR in promoting sprouting responses, we coinactivate PTEN and CSPGs, and demonstrate that this combination leads to an additive increase in axonal sprouting compared with single treatments. Our findings reveal a developmental switch in mTOR dependency for inducing axonal sprouting, and indicate that PTEN deletion in adult neurons neither recapitulates the regrowth program of postnatal animals, nor is sufficient to completely overcome an inhibitory environment. Accordingly, exploiting mTOR levels by targeting PTEN combined with CSPG degradation represents a promising strategy to promote extensive axonal plasticity in adult mammals.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 11/2014; 34(46):15347-55. DOI:10.1523/JNEUROSCI.1935-14.2014 · 6.34 Impact Factor
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    • "For example, although STAT3 deletion has no significant effect on the survival of intact motoneurons, its loss significantly increases the death of motoneurons after facial nerve injury (Schweizer et al., 2002). In addition, SOCS3 deletion in retinal ganglion cells promotes neuronal survival in addition to axon regeneration after optic nerve injury (Smith et al., 2009; Sun et al., 2011), suggesting that STAT3 might act as an important survival promotor especially after injury . However, despite some biochemical studies, how STATs regulate neuronal survival is less understood. "
    Experimental Neurology 11/2014; 263. DOI:10.1016/j.expneurol.2014.10.024 · 4.70 Impact Factor
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