title: Restoration of skilled locomotion by sprouting corticospinal axons induced by co-deletion of PTEN and SOCS3.
abstract: The limited rewiring of the corticospinal tract (CST) only partially compensates the lost functions after stroke, brain trauma and spinal cord injury. Therefore it is important to develop new therapies to enhance the compensatory circuitry mediated by spared CST axons. Here by using a unilateral pyramidotomy model, we find that deletion of cortical suppressor of cytokine signaling 3 (SOCS3), a negative regulator of cytokine-activated pathway, promotes sprouting of uninjured CST axons to the denervated spinal cord. A likely trigger of such sprouting is ciliary neurotrophic factor (CNTF) expressed in local spinal neurons. Such sprouting can be further enhanced by deletion of phosphatase and tensin homolog (PTEN), a mechanistic target of rapamycin (mTOR) negative regulator, resulting in significant recovery of skilled locomotion. Ablation of the corticospinal neurons with sprouting axons abolishes the improved behavioural performance. Furthermore, by optogenetics-based specific CST stimulation, we show a direct limb motor control by sprouting CST axons, providing direct evidence for the reformation of a functional circuit.
authors.affiliation: F.M. Kirby Neurobiology Center, Children's Hospital and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Duo
authors.initials: D
authors.lastname: Jin
authors.affiliation: F.M. Kirby Neurobiology Center, Children's Hospital and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: F.M. Kirby Neurobiology Center, Children's Hospital and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Sun
authors.affiliation: F.M. Kirby Neurobiology Center, Children's Hospital and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Xuhua
authors.initials: X
authors.lastname: Wang
authors.affiliation: F.M. Kirby Neurobiology Center, Children's Hospital and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Liu
authors.affiliation: F.M. Kirby Neurobiology Center, Children's Hospital and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: He
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D020934:Ciliary Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D055786:Gene Knockout Techniques; D007150:Immunohistochemistry; D008124:Locomotion / Q000235:genetics*; D051379:Mice; D009416:Nerve Regeneration / Q000235:genetics*; D009474:Neurons / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D011712:Pyramidal Tracts / Q000293:injuries / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D020127:Recovery of Function / Q000235:genetics*; D013119:Spinal Cord Injuries / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D020934:Ciliary Neurotrophic Factor; D012333:RNA, Messenger; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse