RESUMEN
Failure of axon regeneration after central nervous system (CNS) injuries results in permanent functional deficits. Numerous studies in the past suggested that blocking extracellular inhibitory influences alone is insufficient to allow the majority of injured axons to regenerate, pointing to the importance of revisiting the hypothesis that diminished intrinsic regenerative ability critically underlies regeneration failure. Recent studies in different species and using different injury models have started to reveal important cellular and molecular mechanisms within neurons that govern axon regeneration. This review summarizes these observations and discusses possible strategies for stimulating axon regeneration and perhaps functional recovery after CNS injury.
Asunto(s)
Axones/fisiología , Enfermedades del Sistema Nervioso Central/patología , Enfermedades del Sistema Nervioso Central/fisiopatología , Regeneración Nerviosa/fisiología , Neuronas/patología , Animales , Transporte Axonal/fisiología , AMP Cíclico/metabolismo , Citocinas/metabolismo , Humanos , Inflamación/etiología , Modelos Neurológicos , Neuronas/clasificación , Neuronas/metabolismo , Proteínas Supresoras de la Señalización de Citocinas/metabolismoRESUMEN
Despite the essential role of the corticospinal tract (CST) in controlling voluntary movements, successful regeneration of large numbers of injured CST axons beyond a spinal cord lesion has never been achieved. We found that PTEN/mTOR are critical for controlling the regenerative capacity of mouse corticospinal neurons. After development, the regrowth potential of CST axons was lost and this was accompanied by a downregulation of mTOR activity in corticospinal neurons. Axonal injury further diminished neuronal mTOR activity in these neurons. Forced upregulation of mTOR activity in corticospinal neurons by conditional deletion of Pten, a negative regulator of mTOR, enhanced compensatory sprouting of uninjured CST axons and enabled successful regeneration of a cohort of injured CST axons past a spinal cord lesion. Furthermore, these regenerating CST axons possessed the ability to reform synapses in spinal segments distal to the injury. Thus, modulating neuronal intrinsic PTEN/mTOR activity represents a potential therapeutic strategy for promoting axon regeneration and functional repair after adult spinal cord injury.
Asunto(s)
Regeneración Nerviosa/fisiología , Neuronas/fisiología , Fosfohidrolasa PTEN/metabolismo , Tractos Piramidales/fisiología , Envejecimiento/fisiología , Animales , Axones/fisiología , Axones/ultraestructura , Vértebras Cervicales , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Bulbo Raquídeo/fisiología , Bulbo Raquídeo/fisiopatología , Ratones , Ratones Transgénicos , Neuronas/ultraestructura , Fosfohidrolasa PTEN/deficiencia , Fosfohidrolasa PTEN/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Tractos Piramidales/fisiopatología , Tractos Piramidales/ultraestructura , Corteza Somatosensorial/fisiología , Corteza Somatosensorial/fisiopatología , Médula Espinal/fisiología , Médula Espinal/fisiopatología , Médula Espinal/ultraestructura , Traumatismos de la Médula Espinal/fisiopatología , Sinapsis/fisiología , Sinapsis/ultraestructura , Serina-Treonina Quinasas TOR , Vértebras TorácicasRESUMEN
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.
Asunto(s)
Regeneración Nerviosa/genética , Traumatismos del Nervio Óptico/fisiopatología , Proteínas Supresoras de la Señalización de Citocinas/deficiencia , Análisis de Varianza , Animales , Animales Recién Nacidos , Axones/efectos de los fármacos , Axones/metabolismo , Axones/patología , Proteínas Portadoras/metabolismo , Toxina del Cólera/metabolismo , Factor Neurotrófico Ciliar/genética , Factor Neurotrófico Ciliar/farmacología , Receptor gp130 de Citocinas/deficiencia , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica/genética , Proteínas Fluorescentes Verdes/genética , Inyecciones Intraventriculares/métodos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Regeneración Nerviosa/efectos de los fármacos , Regeneración Nerviosa/fisiología , Traumatismos del Nervio Óptico/tratamiento farmacológico , Traumatismos del Nervio Óptico/genética , Técnicas de Cultivo de Órganos , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Células Ganglionares de la Retina/patología , Células Ganglionares de la Retina/fisiología , Proteína 3 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas/fisiología , Serina-Treonina Quinasas TOR , Factores de Tiempo , Tubulina (Proteína)/metabolismoRESUMEN
The failure of axons to regenerate is a major obstacle for functional recovery after central nervous system (CNS) injury. Removing extracellular inhibitory molecules results in limited axon regeneration in vivo. To test for the role of intrinsic impediments to axon regrowth, we analyzed cell growth control genes using a virus-assisted in vivo conditional knockout approach. Deletion of PTEN (phosphatase and tensin homolog), a negative regulator of the mammalian target of rapamycin (mTOR) pathway, in adult retinal ganglion cells (RGCs) promotes robust axon regeneration after optic nerve injury. In wild-type adult mice, the mTOR activity was suppressed and new protein synthesis was impaired in axotomized RGCs, which may contribute to the regeneration failure. Reactivating this pathway by conditional knockout of tuberous sclerosis complex 1, another negative regulator of the mTOR pathway, also leads to axon regeneration. Thus, our results suggest the manipulation of intrinsic growth control pathways as a therapeutic approach to promote axon regeneration after CNS injury.