SOCS3 Deletion Promotes Optic Nerve Regeneration In Vivo

Axon regeneration failure accounts for permanent functional deficits following CNS injury in adult mammals. However, the underlying mechanisms remain elusive. In analyzing axon regeneration in different mutant mouse lines, we discovered that deletion of suppressor of cytokine signaling 3 (SOCS3) in adult retinal ganglion cells (RGCs) promotes robust regeneration of injured optic nerve axons. This regeneration-promoting effect is efficiently blocked in SOCS3-gp130 double-knockout mice, suggesting that SOCS3 deletion promotes axon regeneration via a gp130-dependent pathway. Consistently, a transient upregulation of ciliary neurotrophic factor (CNTF) was observed within the retina following optic nerve injury. Intravitreal application of CNTF further enhances axon regeneration from SOCS3-deleted RGCs. Together, our results suggest that compromised responsiveness to injury-induced growth factors in mature neurons contributes significantly to regeneration failure. Thus, developing strategies to modulate negative signaling regulators may be an efficient strategy of promoting axon regeneration after CNS injury.

[1]  R. B. Hart,et al.  The Cytokine Interleukin-6 Is Sufficient But Not Necessary to Mimic the Peripheral Conditioning Lesion Effect on Axonal Growth , 2006, The Journal of Neuroscience.

[2]  A. Yoshimura,et al.  Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity , 2004, Nature Medicine.

[3]  Elise J. Dallimore,et al.  Cytokine-induced SOCS expression is inhibited by cAMP analogue: Impact on regeneration in injured retina , 2009, Molecular and Cellular Neuroscience.

[4]  D. Fischer,et al.  Astrocyte-derived CNTF switches mature RGCs to a regenerative state following inflammatory stimulation. , 2007, Brain : a journal of neurology.

[5]  S. Thanos,et al.  Cataractogenic lens injury prevents traumatic ganglion cell death and promotes axonal regeneration both in vivo and in culture. , 2000, Investigative ophthalmology & visual science.

[6]  M. Filbin,et al.  Neuronal Cyclic AMP Controls the Developmental Loss in Ability of Axons to Regenerate , 2001, The Journal of Neuroscience.

[7]  S. McMahon,et al.  Leukemia Inhibitory Factor Determines the Growth Status of Injured Adult Sensory Neurons , 2001, The Journal of Neuroscience.

[8]  Jeffrey L Goldberg,et al.  Amacrine-Signaled Loss of Intrinsic Axon Growth Ability by Retinal Ganglion Cells , 2002, Science.

[9]  R. Marienfeld,et al.  Exogenous CNTF stimulates axon regeneration of retinal ganglion cells partially via endogenous CNTF , 2009, Molecular and Cellular Neuroscience.

[10]  Milos Pekny,et al.  Re-establishing the regenerative potential of central nervous system axons in postnatal mice , 2005, Journal of Cell Science.

[11]  F. Holsboer,et al.  Peripheral and central regulation of IL-6 gene expression in endotoxin-treated rats. , 1992, Endocrine Regulations.

[12]  Noam Y. Harel,et al.  Can regenerating axons recapitulate developmental guidance during recovery from spinal cord injury? , 2006, Nature Reviews Neuroscience.

[13]  A. Harvey,et al.  Cellular Mechanisms Associated with Spontaneous and Ciliary Neurotrophic Factor-cAMP-Induced Survival and Axonal Regeneration of Adult Retinal Ganglion Cells , 2004, The Journal of Neuroscience.

[14]  M. Filbin.  Recapitulate development to promote axonal regeneration: good or bad approach? , 2006, Philosophical Transactions of the Royal Society B: Biological Sciences.

[15]  C. Woolf,et al.  Regeneration of Dorsal Column Fibers into and beyond the Lesion Site following Adult Spinal Cord Injury , 1999, Neuron.

[16]  W. Snider,et al.  Intracellular control of developmental and regenerative axon growth , 2006, Philosophical Transactions of the Royal Society B: Biological Sciences.

[17]  W. Alexander,et al.  Socs3 maintains the specificity of biological responses to cytokine signals during granulocyte and macrophage differentiation. , 2008, Experimental hematology.

[18]  L. Benowitz,et al.  Lens Injury Stimulates Axon Regeneration in the Mature Rat Optic Nerve , 2000, The Journal of Neuroscience.

[19]  A. Harvey,et al.  Cooperative effects of bcl‐2 and AAV‐mediated expression of CNTF on retinal ganglion cell survival and axonal regeneration in adult transgenic mice , 2006, The European journal of neuroscience.

[20]  M. Schwab,et al.  Degeneration and regeneration of axons in the lesioned spinal cord. , 1996, Physiological reviews.

[21]  H. Yip,et al.  CNTF, not other trophic factors, promotes axonal regeneration of axotomized retinal ganglion cells in adult hamsters. , 1999, Investigative ophthalmology & visual science.

[22]  Marc Tessier-Lavigne,et al.  Regeneration of the adult central nervous system , 2005, Current Biology.

[23]  Zhigang He,et al.  Glial inhibition of CNS axon regeneration , 2006, Nature Reviews Neuroscience.

[24]  Zhigang He,et al.  Promoting Axon Regeneration in the Adult CNS by Modulation of the PTEN/mTOR Pathway , 2008, Science.

[25]  Ping Wang,et al.  Suppressor of Cytokine Signaling-3 Suppresses the Ability of Activated Signal Transducer and Activator of Transcription-3 to Stimulate Neurite Growth in Rat Primary Sensory Neurons , 2006, The Journal of Neuroscience.

[26]  J. Johnston,et al.  Tyrosine-phosphorylated SOCS-3 inhibits STAT activation but binds to p120 RasGAP and activates Ras , 2001, Nature Cell Biology.

[27]  R. Mohney,et al.  Changes in neuropeptide phenotype after axotomy of adult peripheral neurons and the role of leukemia inhibitory factor. , 1996, Perspectives on developmental neurobiology.

[28]  K. Rajewsky,et al.  Postnatally Induced Inactivation of gp130 in Mice Results in Neurological, Cardiac, Hematopoietic, Immunological, Hepatic, and Pulmonary Defects , 1998, The Journal of experimental medicine.

[29]  L. Reichardt,et al.  Neurotrophin-regulated signalling pathways , 2006, Philosophical Transactions of the Royal Society B: Biological Sciences.

[30]  J. Blenis,et al.  Molecular mechanisms of mTOR-mediated translational control , 2009, Nature Reviews Molecular Cell Biology.

[31]  R. Vejsada,et al.  Cardiotrophin-1, a Cytokine Present in Embryonic Muscle, Supports Long-Term Survival of Spinal Motoneurons , 1996, Neuron.

[32]  S. Akira,et al.  Conditional gene ablation of Stat3 reveals differential signaling requirements for survival of motoneurons during development and after nerve injury in the adult , 2002, The Journal of cell biology.

[33]  H. Rohrer,et al.  The dependence on gp130 cytokines of axotomy induced neuropeptide expression in adult sympathetic neurons , 2009, Developmental neurobiology.

[34]  J. Silver,et al.  CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure , 2008, Experimental Neurology.

[35]  B. Barres,et al.  The relationship between neuronal survival and regeneration. , 2000, Annual review of neuroscience.

[36]  M. Koltzenburg,et al.  Axoplasmic Importins Enable Retrograde Injury Signaling in Lesioned Nerve , 2003, Neuron.

[37]  E. Godaux,et al.  Neuronal Deficiency of Presenilin 1 Inhibits Amyloid Plaque Formation and Corrects Hippocampal Long-Term Potentiation But Not a Cognitive Defect of Amyloid Precursor Protein [V717I] Transgenic Mice , 2002, The Journal of Neuroscience.

[38]  M. Tuszynski,et al.  Delivery of hyper‐interleukin‐6 to the injured spinal cord increases neutrophil and macrophage infiltration and inhibits axonal growth , 2002, The Journal of comparative neurology.

[39]  W. Snider,et al.  Different Signaling Pathways Mediate Regenerative versus Developmental Sensory Axon Growth , 2001, The Journal of Neuroscience.

[40]  Does CNTF mediate the effect of intraocular inflammation on optic nerve regeneration? , 2008, Brain : a journal of neurology.

[41]  Y. Fukuda,et al.  Intravitreal injections of neurotrophic factors and forskolin enhance survival and axonal regeneration of axotomized β ganglion cells in cat retina , 2003, Neuroscience.