title: Sustained axon regeneration induced by co-deletion of PTEN and SOCS3.
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.
authors: F.M. Kirby Neurobiology Center, Children's Hospital, Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
authors: Fang
authors: F
authors: Sun
authors: Kevin K
authors: KK
authors: Park
authors: Stephane
authors: S
authors: Belin
authors: Dongqing
authors: D
authors: Wang
authors: Tao
authors: T
authors: Lu
authors: Gang
authors: G
authors: Chen
authors: Kang
authors: K
authors: Zhang
authors: Cecil
authors: C
authors: Yeung
authors: Guoping
authors: G
authors: Feng
authors: Bruce A
authors: BA
authors: Yankner
authors: Zhigang
authors: Z
authors: He
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology / Q000502:physiology*; D048708:Cell Growth Processes / Q000235:genetics; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000502:physiology*; D009900:Optic Nerve / Q000166:cytology / Q000254:growth & development / Q000473:pathology; D020221:Optic Nerve Injuries / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D012165:Retinal Ganglion Cells / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency* / Q000235:genetics
chemical_list: D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse