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1.
J Neurosci ; 31(16): 5977-88, 2011 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-21508223

RESUMO

Stroke is the leading cause of disability in much of the world, with few treatment options available. Following unilateral stroke in rats, inosine, a naturally occurring purine nucleoside, stimulates the growth of projections from the undamaged hemisphere into denervated areas of the spinal cord and improves skilled use of the impaired forelimb. Inosine augments neurons' intrinsic growth potential by activating Mst3b, a component of the signal transduction pathway through which trophic factors regulate axon outgrowth. The present study investigated whether inosine would complement the effects of treatments that promote plasticity through other mechanisms. Following unilateral stroke in the rat forelimb motor area, inosine combined with NEP1-40, a Nogo receptor antagonist, doubled the number of axon branches extending from neurons in the intact hemisphere into the denervated side of the spinal cord compared with either treatment alone, and restored rats' level of skilled reaching using the impaired forepaw to preoperative levels. Similar functional improvements were seen when inosine was combined with environmental enrichment (EE). The latter effect was associated with changes in gene expression in layer 5 pyramidal neurons of the undamaged cortex well beyond those seen with inosine or EE alone. Inosine is now in clinical trials for other indications, making it an attractive candidate for the treatment of stroke patients.


Assuntos
Membro Anterior/efeitos dos fármacos , Inosina/uso terapêutico , Proteínas da Mielina/uso terapêutico , Neurônios/efeitos dos fármacos , Fragmentos de Peptídeos/uso terapêutico , Recuperação de Função Fisiológica/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Axônios/efeitos dos fármacos , Axônios/fisiologia , Meio Ambiente , Membro Anterior/fisiopatologia , Inosina/farmacologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Movimento/efeitos dos fármacos , Movimento/fisiologia , Proteínas da Mielina/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Fragmentos de Peptídeos/farmacologia , Ratos , Recuperação de Função Fisiológica/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiopatologia , Acidente Vascular Cerebral/fisiopatologia
2.
J Biol Chem ; 286(20): 18026-36, 2011 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-21454605

RESUMO

Nogo-A limits axon regeneration and functional recovery after central nervous system injury in adult mammals. Three regions of Nogo-A (Nogo-A-24, Nogo-66, and Nogo-C39) interact with the neuronal Nogo-66 receptor 1 (NgR1). Nogo-66 also interacts with a structurally unrelated cell surface receptor, paired immunoglobulin-like receptor (PirB). We show here that the other two NgR1-interacting domains, Nogo-A-24 and Nogo-C39, also bind to PirB with high affinity. A purified 22-kDa protein containing all three NgR1- and PirB-interacting domains (Nogo-22) is a substantially more potent growth cone-collapsing molecule than Nogo-66 for chick dorsal root ganglion neurons and mature cortical neurons. Moreover, Nogo-22 inhibits axon regeneration of mature cortical neurons in vitro more potently than does Nogo-66. Although all three NgR1-interacting domains of Nogo-A also interact with PirB, expression of PirB in mature cortical cultures is nearly undetectable. Consistent with a relatively minor role for PirB in mature cortical neurons, Nogo-22 inhibition of axon regeneration is abolished by genetic deletion of NgR1. Thus, NgR1 is the predominant receptor for Nogo-22 in regenerating cortical neurons.


Assuntos
Axônios/metabolismo , Córtex Cerebral/metabolismo , Proteínas da Mielina/metabolismo , Receptores de Superfície Celular/metabolismo , Regeneração/fisiologia , Animais , Células Cultivadas , Córtex Cerebral/citologia , Galinhas , Chlorocebus aethiops , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Gânglios Espinais/citologia , Gânglios Espinais/metabolismo , Humanos , Camundongos , Proteínas da Mielina/genética , Proteínas Nogo , Receptor Nogo 1 , Estrutura Terciária de Proteína , Receptores de Superfície Celular/genética , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo
3.
J Neurosci ; 30(20): 6825-37, 2010 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-20484625

RESUMO

Functional recovery after adult CNS damage is limited in part by myelin inhibitors of axonal regrowth. Three molecules, Nogo-A, MAG, and OMgp, are produced by oligodendrocytes and share neuronal receptor mechanisms through NgR1 and PirB. While each has an axon-inhibitory role in vitro, their in vivo interactions and relative potencies have not been defined. Here, we compared mice singly, doubly, or triply mutant for these three myelin inhibitor proteins. The myelin extracted from Nogo-A mutant mice is less inhibitory for axons than is that from wild-type mice, but myelin lacking MAG and OMgp is indistinguishable from control. However, myelin lacking all three inhibitors is less inhibitory than Nogo-A-deficient myelin, uncovering a redundant and synergistic role for all three proteins in axonal growth inhibition. Spinal cord injury studies revealed an identical in vivo hierarchy of these three myelin proteins. Loss of Nogo-A allows corticospinal and raphespinal axon growth above and below the injury, as well as greater behavioral recovery than in wild-type or heterozygous mutant mice. In contrast, deletion of MAG and OMgp stimulates neither axonal growth nor enhanced locomotion. The triple-mutant mice exhibit greater axonal growth and improved locomotion, consistent with a principal role for Nogo-A and synergistic actions for MAG and OMgp, presumably through shared receptors. These data support the hypothesis that targeting all three myelin ligands, as with NgR1 decoy receptor, provides the optimal chance for overcoming myelin inhibition and improving neurological function.


Assuntos
Proteínas da Mielina/metabolismo , Glicoproteína Associada a Mielina/metabolismo , Neurônios/patologia , Receptores de Superfície Celular/metabolismo , Recuperação de Função Fisiológica/fisiologia , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia , Análise de Variância , Animais , Biotina/análogos & derivados , Biotina/metabolismo , Células Cultivadas , Dextranos/metabolismo , Modelos Animais de Doenças , Feminino , Lateralidade Funcional/fisiologia , Proteínas Ligadas por GPI , Gânglios Espinais/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação/genética , Proteínas da Mielina/genética , Glicoproteína Associada a Mielina/genética , Glicoproteína Mielina-Oligodendrócito , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nogo , Tratos Piramidais/patologia , Receptores de Superfície Celular/genética , Receptores de Serotonina/metabolismo , Recuperação de Função Fisiológica/genética
4.
Cell Rep ; 36(10): 109666, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34496254

RESUMO

Although axonal damage induces rapid changes in gene expression in primary sensory neurons, it remains unclear how this process is initiated. The transcription factor ATF3, one of the earliest genes responding to nerve injury, regulates expression of downstream genes that enable axon regeneration. By exploiting ATF3 reporter systems, we identify topoisomerase inhibitors as ATF3 inducers, including camptothecin. Camptothecin increases ATF3 expression and promotes neurite outgrowth in sensory neurons in vitro and enhances axonal regeneration after sciatic nerve crush in vivo. Given the action of topoisomerases in producing DNA breaks, we determine that they do occur immediately after nerve damage at the ATF3 gene locus in injured sensory neurons and are further increased after camptothecin exposure. Formation of DNA breaks in injured sensory neurons and enhancement of it pharmacologically may contribute to the initiation of those transcriptional changes required for peripheral nerve regeneration.


Assuntos
Fator 3 Ativador da Transcrição/metabolismo , Axônios/metabolismo , Quebras de DNA/efeitos dos fármacos , DNA Topoisomerases Tipo I/metabolismo , Traumatismos dos Nervos Periféricos/metabolismo , Células Receptoras Sensoriais/metabolismo , Animais , DNA Topoisomerases Tipo I/efeitos dos fármacos , Expressão Gênica/fisiologia , Camundongos Endogâmicos C57BL , Regeneração Nervosa/efeitos dos fármacos , Regeneração Nervosa/fisiologia , Crescimento Neuronal/fisiologia , Nervo Isquiático/metabolismo
5.
Mol Neurobiol ; 56(6): 3948-3957, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30232777

RESUMO

Axotomy results in permanent loss of function after brain and spinal cord injuries due to the minimal regenerative propensity of the adult central nervous system (CNS). To identify pharmacological enhancers of axon regeneration, 960 compounds were screened for cortical neuron axonal regrowth using an in vitro cortical scrape assay. Diltiazem, verapamil, and bromopride were discovered to facilitate axon regeneration in rat cortical cultures, in the presence of chondroitin sulfate proteoglycans (CSPGs). Diltiazem, an L-type calcium channel blocker (L-CCB), also promotes axon outgrowth in adult primary mouse dorsal root ganglion (DRG) and induced human sensory (iSensory) neurons.


Assuntos
Axônios/fisiologia , Diltiazem/farmacologia , Regeneração Nervosa/efeitos dos fármacos , Amidas/farmacologia , Animais , Axônios/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/metabolismo , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Sinergismo Farmacológico , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Piridinas/farmacologia , Ratos Sprague-Dawley
6.
Cell Rep ; 24(7): 1865-1879.e9, 2018 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-30110642

RESUMO

We generated a knockout mouse for the neuronal-specific ß-tubulin isoform Tubb3 to investigate its role in nervous system formation and maintenance. Tubb3-/- mice have no detectable neurobehavioral or neuropathological deficits, and upregulation of mRNA and protein of the remaining ß-tubulin isotypes results in equivalent total ß-tubulin levels in Tubb3-/- and wild-type mice. Despite similar levels of total ß-tubulin, adult dorsal root ganglia lacking TUBB3 have decreased growth cone microtubule dynamics and a decreased neurite outgrowth rate of 22% in vitro and in vivo. The effect of the 22% slower growth rate is exacerbated for sensory recovery, where fibers must reinnervate the full volume of the skin to recover touch function. Overall, these data reveal that, while TUBB3 is not required for formation of the nervous system, it has a specific role in the rate of peripheral axon regeneration that cannot be replaced by other ß-tubulins.


Assuntos
Regeneração Nervosa/genética , Crescimento Neuronal/genética , Isoformas de Proteínas/genética , Tubulina (Proteína)/genética , Potenciais de Ação/fisiologia , Animais , Feminino , Gânglios Espinais/lesões , Gânglios Espinais/metabolismo , Regulação da Expressão Gênica , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Knockout , Microtúbulos/metabolismo , Microtúbulos/ultraestrutura , Plasticidade Neuronal/genética , Isoformas de Proteínas/metabolismo , Transdução de Sinais , Tubulina (Proteína)/deficiência
7.
Cell Rep ; 20(5): 1136-1147, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28768198

RESUMO

Peripheral nerve regeneration after injury requires a broad program of transcriptional changes. We investigated the basis for the enhanced nerve regenerative capacity of the CAST/Ei mouse strain relative to C57BL/6 mice. RNA sequencing of dorsal root ganglia (DRG) showed a CAST/Ei-specific upregulation of Ascl1 after injury. Ascl1 overexpression in DRG neurons of C57BL/6 mice enhanced their neurite outgrowth. Ascl1 is regulated by miR-7048-3p, which is downregulated in CAST/Ei mice. Inhibition of miR-7048-3p enhances neurite outgrowth. Following injury, CAST/Ei neurons largely retained their mature neuronal profile as determined by single-cell RNA- seq, whereas the C57BL/6 neurons acquired an immature profile. These findings suggest that one facet of the enhanced regenerative phenotype is preservation of neuronal identity in response to injury.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Regeneração Nervosa , Neuritos/metabolismo , Traumatismos dos Nervos Periféricos/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Masculino , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Neuritos/patologia , Traumatismos dos Nervos Periféricos/genética , Traumatismos dos Nervos Periféricos/patologia
8.
Neuron ; 89(5): 956-70, 2016 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-26898779

RESUMO

The regenerative capacity of the injured CNS in adult mammals is severely limited, yet axons in the peripheral nervous system (PNS) regrow, albeit to a limited extent, after injury. We reasoned that coordinate regulation of gene expression in injured neurons involving multiple pathways was central to PNS regenerative capacity. To provide a framework for revealing pathways involved in PNS axon regrowth after injury, we applied a comprehensive systems biology approach, starting with gene expression profiling of dorsal root ganglia (DRGs) combined with multi-level bioinformatic analyses and experimental validation of network predictions. We used this rubric to identify a drug that accelerates DRG neurite outgrowth in vitro and optic nerve outgrowth in vivo by inducing elements of the identified network. The work provides a functional genomics foundation for understanding neural repair and proof of the power of such approaches in tackling complex problems in nervous system biology.


Assuntos
Axônios/fisiologia , Gânglios Espinais/citologia , Regeneração Nervosa/fisiologia , Neurônios/citologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Animais , Animais Recém-Nascidos , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , Imunoprecipitação da Cromatina , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Glutamina-Frutose-6-Fosfato Transaminase (Isomerizante) , Canais Iônicos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos , Regeneração Nervosa/genética , Transferases de Grupos Nitrogenados/genética , Transferases de Grupos Nitrogenados/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Proteína cdc42 de Ligação ao GTP/genética , Proteína cdc42 de Ligação ao GTP/metabolismo
9.
Cell Rep ; 16(6): 1664-1676, 2016 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-27477284

RESUMO

How can cells sense their own size to coordinate biosynthesis and metabolism with their growth needs? We recently proposed a motor-dependent bidirectional transport mechanism for axon length and cell size sensing, but the nature of the motor-transported size signals remained elusive. Here, we show that motor-dependent mRNA localization regulates neuronal growth and cycling cell size. We found that the RNA-binding protein nucleolin is associated with importin ß1 mRNA in axons. Perturbation of nucleolin association with kinesins reduces its levels in axons, with a concomitant reduction in axonal importin ß1 mRNA and protein levels. Strikingly, subcellular sequestration of nucleolin or importin ß1 enhances axonal growth and causes a subcellular shift in protein synthesis. Similar findings were obtained in fibroblasts. Thus, subcellular mRNA localization regulates size and growth in both neurons and cycling cells.


Assuntos
Tamanho Celular , Neurônios Motores/metabolismo , Fosfoproteínas/metabolismo , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Axônios/metabolismo , Camundongos Transgênicos , Neurogênese , Biossíntese de Proteínas/fisiologia , Nucleolina
10.
Nat Neurosci ; 18(1): 17-24, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25420066

RESUMO

Reprogramming somatic cells from one cell fate to another can generate specific neurons suitable for disease modeling. To maximize the utility of patient-derived neurons, they must model not only disease-relevant cell classes, but also the diversity of neuronal subtypes found in vivo and the pathophysiological changes that underlie specific clinical diseases. We identified five transcription factors that reprogram mouse and human fibroblasts into noxious stimulus-detecting (nociceptor) neurons. These recapitulated the expression of quintessential nociceptor-specific functional receptors and channels found in adult mouse nociceptor neurons, as well as native subtype diversity. Moreover, the derived nociceptor neurons exhibited TrpV1 sensitization to the inflammatory mediator prostaglandin E2 and the chemotherapeutic drug oxaliplatin, modeling the inherent mechanisms underlying inflammatory pain hypersensitivity and painful chemotherapy-induced neuropathy. Using fibroblasts from patients with familial dysautonomia (hereditary sensory and autonomic neuropathy type III), we found that the technique was able to reveal previously unknown aspects of human disease phenotypes in vitro.


Assuntos
Fibroblastos , Modelos Neurológicos , Nociceptores , Dor/fisiopatologia , Células Receptoras Sensoriais , Animais , Disautonomia Familiar/patologia , Fenômenos Eletrofisiológicos/fisiologia , Humanos , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Doenças do Sistema Nervoso Periférico/patologia , Fatores de Transcrição
11.
Neuron ; 86(5): 1215-27, 2015 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-26004914

RESUMO

Axon regeneration in the CNS requires reactivating injured neurons' intrinsic growth state and enabling growth in an inhibitory environment. Using an inbred mouse neuronal phenotypic screen, we find that CAST/Ei mouse adult dorsal root ganglion neurons extend axons more on CNS myelin than the other eight strains tested, especially when pre-injured. Injury-primed CAST/Ei neurons also regenerate markedly in the spinal cord and optic nerve more than those from C57BL/6 mice and show greater sprouting following ischemic stroke. Heritability estimates indicate that extended growth in CAST/Ei neurons on myelin is genetically determined, and two whole-genome expression screens yield the Activin transcript Inhba as most correlated with this ability. Inhibition of Activin signaling in CAST/Ei mice diminishes their CNS regenerative capacity, whereas its activation in C57BL/6 animals boosts regeneration. This screen demonstrates that mammalian CNS regeneration can occur and reveals a molecular pathway that contributes to this ability.


Assuntos
Axônios/fisiologia , Gânglios Espinais/fisiologia , Regeneração Nervosa/fisiologia , Neuropatia Ciática/fisiopatologia , Traumatismos da Medula Espinal/fisiopatologia , Animais , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Endogâmicos NOD , Neuropatia Ciática/patologia , Traumatismos da Medula Espinal/patologia
13.
Results Probl Cell Differ ; 48: 339-51, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19582408

RESUMO

Axon regeneration in the mature mammalian central nervous system (CNS) is extremely limited after injury. Consequently, functional deficits persist after spinal cord injury (SCI), traumatic brain injury, stroke, and related conditions that involve axonal disconnection. This situation differs from that in the mammalian peripheral nervous system (PNS), where long-distance axon regeneration and substantial functional recovery can occur in the adult. Both extracellular molecules and the intrinsic growth capacity of the neuron influence regenerative success. This chapter discusses determinants of axon regeneration in the PNS and CNS.


Assuntos
Axônios/fisiologia , Sistema Nervoso Central/fisiologia , Regeneração Nervosa , Sistema Nervoso Periférico/fisiologia , Animais , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Proteínas Ricas em Prolina do Estrato Córneo/genética , Proteínas Ricas em Prolina do Estrato Córneo/metabolismo , Humanos , Transdução de Sinais
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