Article

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

ABSTRACT

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.
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    • "Furthermore, previous reports have demonstrated that mTOR activation promotes axon regeneration in vivo (Park et al., 2008; Smith et al., 2009; Liu et al., 2010; Sun et al., 2011). The activation of mTOR signalling results in phosphorylation of ribosomal protein S6 (p-S6); this phosphorylation of S6 has been correlated positively with axon regeneration in the mature CNS (Park et al., 2008; Smith et al., 2009; Liu et al., 2010; Sun et al., 2011). It is reported here that unilateral injections of ET-1 in the mouse brain result in skilled motor impairment and forelimb asymmetry. "
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    Full-text · Article · Oct 2015 · European Journal of Neuroscience
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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: eLife digest In the nervous system, cells called neurons carry information around the body. These cells have long thin projections called axons that allow the information to pass very quickly along the cell to junctions with other neurons. Neurons in adult mammals are limited in their ability to regenerate, so any damage to axons, for example, due to a stroke or a brain injury, tends to be permanent. Therefore, an important goal in neuroscience research is to discover the genes and proteins that are involved in regenerating axons as this may make it possible to develop new therapies. An internal scaffold called the cytoskeleton supports the three-dimensional shape of the axons. Changes in the cytoskeleton are required to allow neurons to regenerate axons after injury, and drugs that stabilize filaments called microtubules in the cytoskeleton can promote these changes. Chen et al. used a technique called laser microsurgery to sever individual axons in a roundworm known as C. elegans and then observed whether these axons could regenerate. The experiments reveal that a protein called EFA-6 blocks the regeneration of neurons by preventing rearrangements in the cytoskeleton. EFA-6 is normally found at the membrane that surrounds the neuron. However, Chen et al. show that when the axon is damaged, this protein rapidly moves to areas near the ends of microtubule filaments. EFA-6 interacts with two other proteins that are associated with microtubules and are required for axons to be able to regenerate. Chen et al.'s findings demonstrate that several proteins that regulate microtubule filaments play a key role in regenerating axons. All three of these proteins are found in humans and other animals so they have the potential to be targeted by drug therapies in future. The next challenge is to understand the details of how EFA-6 activity is affected by axon injury, and how this alters the cytoskeleton. DOI: http://dx.doi.org/10.7554/eLife.08695.002
    Full-text · Article · Sep 2015 · eLife Sciences
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