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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    • "Effects of PTEN Deletion We reasoned that the direct effects of DCLK2 overexpression might be mainly limited to the axon cytoskeleton, and it might have functional interactions with other identified regeneration regulators. As our previous studies indicated that manipulating the mTOR pathway could enhance neuronal regeneration (Liu et al., 2010; Park et al., 2008; Sun et al., 2011; Zukor et al., 2013), we tested the combinatorial outcomes of DCLK2 overexpression and PTEN deletion. PTEN f/f mice received successive intravitreal injections of AAV2-Cre and AAV2-DCLK2 or control (AAV2-PLAP) viruses (Figures 2A–2C). "
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    ABSTRACT: After axotomy, neuronal survival and growth cone re-formation are required for axon regeneration. We discovered that doublecortin-like kinases (DCLKs), members of the doublecortin (DCX) family expressed in adult retinal ganglion cells (RGCs), play critical roles in both processes, through distinct mechanisms. Overexpression of DCLK2 accelerated growth cone re-formation in vitro and enhanced the initiation and elongation of axon re-growth after optic nerve injury. These effects depended on both the microtubule (MT)-binding domain and the serine-proline-rich (S/P-rich) region of DCXs in-cis in the same molecules. While the MT-binding domain is known to stabilize MT structures, we show that the S/P-rich region prevents F-actin destabilization in injured axon stumps. Additionally, while DCXs synergize with mTOR to stimulate axon regeneration, alone they can promote neuronal survival possibly by regulating the retrograde propagation of injury signals. Multifunctional DCXs thus represent potential targets for promoting both survival and regeneration of injured neurons.
    Neuron 11/2015; 88(4). DOI:10.1016/j.neuron.2015.10.005 · 15.05 Impact Factor
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    • "Recent studies have strongly supported the importance of cell-intrinsic determinants in axon regeneration. Loss of function in cell-intrinsic growth inhibitors such as Phosphatase and Tensin homolog, PTEN, and Suppressor Of Cytokine Signaling-3, SOCS3, can dramatically improve axon regrowth even in the inhibitory CNS environment (Park et al., 2008; Sun et al., 2011). Genetic and pharmacological manipulation of cell autonomous signaling pathways can dramatically improve regrowth of severed axons in various injury paradigms (Moore et al., 2009; Hellal et al., 2011; Sengottuvel et al., 2011; Shin et al., 2012; Watkins et al., 2013; Ruschel et al., 2015). "
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    ABSTRACT: Axon injury triggers a series of changes in the axonal cytoskeleton that are prerequisites for effective axon regeneration. In C. elegans the signaling protein EFA-6 is a potent intrinsic inhibitor of axon regrowth. Here we show that axon injury triggers rapid EFA-6-dependent inhibition of axonal microtubule (MT) dynamics, concomitant with relocalization of EFA-6. EFA-6 relocalization and axon regrowth inhibition require a conserved 18-aa motif in its otherwise intrinsically disordered N-terminal domain. The EFA-6 N-terminus binds the MT-associated proteins TAC-1/Transforming-Acidic-Coiled-Coil, and ZYG-8/Doublecortin-Like-Kinase, both of which are required for regenerative growth cone formation, and which act downstream of EFA-6. After injury TAC-1 and EFA-6 transiently relocalize to sites marked by the MT minus end binding protein PTRN-1/Patronin. We propose that EFA-6 acts as a bifunctional injury-responsive regulator of axonal MT dynamics, acting at the cell cortex in the steady state and at MT minus ends after injury.
    eLife Sciences 09/2015; 4. DOI:10.7554/eLife.08695 · 9.32 Impact Factor
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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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