Scientific Understanding of Consciousness
Axon Regeneration by co-deletion of PTEN and SOCS3
Nature 480, 372–375 (15 December 2011)
Sustained axon regeneration induced by co-deletion of PTEN and SOCS3
F.M. Kirby Neurobiology Center, Children’s Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
Fang Sun, Stephane Belin, Gang Chen, Cecil Yeung & Zhigang He
Miami Project to Cure Paralysis, Department of Neurological Surgery, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA
Kevin K. Park
McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Dongqing Wang & Guoping Feng
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
Tao Lu & Bruce A. Yankner
Shiley Eye Center, University of California at San Diego, La Jolla, California 92093, USA
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.
During development axons reach their targets first through de novo outgrowth in embryos, followed by ‘networked growth’ in which axons elongate with termini tethered to their targets. As animals increase in body size during postnatal and adolescent stages, the distance resulted from the ‘networked growth’ could be much longer than that travelled by the initial de novo growth. After injury in the adult CNS, regenerating axons need to carry out de novo growth over relatively vast distances to reach their targets. Thus, the robustness of axon regeneration, in terms of both speed and duration of axon regrowth, is critical for making functional reconnections in adulthood. Approaches that have been shown to promote axon regeneration in the adult CNS include reducing extracellular inhibitory activity and increasing intrinsic growth ability. However, the extents of axon regeneration observed in these studies are still limited. For example, our previous studies demonstrated that the injured optic nerve could undergo significant axon regeneration after conditional deletion of PTEN or SOCS3 in adult RGCs, but the regrowth only occurred during the first 2 weeks after injury, and then subsided afterwards.
Together, our experiments reveal an important strategy for achieving sustainable de novo axon regrowth in the adult CNS neurons: co-activation of specific protein translations and gene transcriptions by concomitant inactivation of PTEN and SOCS3. Notably, the mTOR activity is maintained and phospho-STAT3 levels are increased in adult peripheral sensory neurons after injury. Thus, the activation states of these two pathways may underlie the differential regenerative abilities of CNS and PNS neurons. However, deletion of PTEN and SOCS3 is not converting the CNS neurons to a PNS-PTEN is similarly expressed in adult PNS neurons and SOCS3 is increased during PNS regeneration. Nonetheless, enhancing mTOR activity through deletion of PTEN or TSC2 also drastically increases axon re-growth in PNS neurons, indicating deletion of PTEN and SOCS3 may make an end-run around different growth-suppressive mechanisms. Considering the formidable long distances that regenerating axons must travel in the adult after injury, the synergistic effects of two different pathways suggest a potential solution to this challenge, making the goal of functional recovery more realistic.
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