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1.
Exp Cell Res ; 368(1): 84-100, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29689278

RESUMO

Development of the spinal cord requires dynamic and tightly controlled expression of numerous transcription factors. Forkhead Box protein J1 (FoxJ1) is a transcription factor involved in ciliogenesis and is specifically expressed in ependymal cells (ECs) in the adult central nervous system. However, using FoxJ1 fate-mapping mouse lines, we observed that FoxJ1 is also transiently expressed by the progenitors of other neural subtypes during development. Moreover, using a knock-in mouse line, we discovered that FoxJ1 is essential for embryonic progenitors to follow a normal developmental trajectory. FoxJ1 loss perturbed embryonic progenitor proliferation and cell fate determination, and resulted in formation of adult ECs having impaired stem cell potential and an inability to respond to spinal cord injury in both male and female animals. Thus, our study uncovers unexpected developmental functions of FoxJ1 in cell fate determination of subsets of neural cells and suggests that FoxJ1 is critical for maintaining the stem cell potential of ECs into adulthood.


Assuntos
Diferenciação Celular/fisiologia , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica/genética , Células-Tronco/citologia , Animais , Epêndima/metabolismo , Feminino , Masculino , Camundongos , Organogênese/fisiologia , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/metabolismo
2.
Glia ; 63(8): 1469-82, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25921491

RESUMO

Stroke and spinal cord injury (SCI) are among the most frequent causes of central nervous system (CNS) dysfunction, affecting millions of people worldwide each year. The personal and financial costs for affected individuals, their families, and the broader communities are enormous. Although the mammalian CNS exhibits little spontaneous regeneration and self-repair, recent discoveries have revealed that subpopulations of glial cells in the adult forebrain subventricular zone and the spinal cord ependymal zone possess neural stem cell properties. These endogenous neural stem cells react to stroke and SCI by contributing a significant number of new neural cells to formation of the glial scar. These findings have raised hopes that new therapeutic strategies can be designed based on appropriate modulation of endogenous neural stem cell responses to CNS injury. Here, we review the responses of forebrain and spinal cord neural stem cells to stroke and SCI, the role of these responses in restricting injury-induced tissue loss, and the possibility of directing these responses to promote anatomical and functional repair of the CNS.


Assuntos
Isquemia Encefálica/fisiopatologia , Células-Tronco Neurais/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Acidente Vascular Cerebral/fisiopatologia , Animais , Isquemia Encefálica/terapia , Epêndima/fisiopatologia , Humanos , Traumatismos da Medula Espinal/terapia , Nicho de Células-Tronco/fisiologia , Acidente Vascular Cerebral/terapia
3.
Proc Natl Acad Sci U S A ; 109(23): E1499-508, 2012 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-22586092

RESUMO

New neurons generated in the adult dentate gyrus are constantly integrated into the hippocampal circuitry and activated during encoding and recall of new memories. Despite identification of extracellular signals that regulate survival and integration of adult-born neurons such as neurotrophins and neurotransmitters, the nature of the intracellular modulators required to transduce those signals remains elusive. Here, we provide evidence of the expression and transcriptional activity of nuclear factor of activated T cell c4 (NFATc4) in hippocampal progenitor cells. We show that NFATc4 calcineurin-dependent activity is required selectively for survival of adult-born neurons in response to BDNF signaling. Indeed, cyclosporin A injection and stereotaxic delivery of the BDNF scavenger TrkB-Fc in the mouse dentate gyrus reduce the survival of hippocampal adult-born neurons in wild-type but not in NFATc4(-/-) mice and do not affect the net rate of neural precursor proliferation and their fate commitment. Furthermore, associated with the reduced survival of adult-born neurons, the absence of NFATc4 leads to selective defects in LTP and in the encoding of hippocampal-dependent spatial memories. Thus, our data demonstrate that NFATc4 is essential in the regulation of adult hippocampal neurogenesis and identify NFATc4 as a central player of BDNF-driven prosurvival signaling in hippocampal adult-born neurons.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Sobrevivência Celular/fisiologia , Hipocampo/citologia , Memória/fisiologia , Fatores de Transcrição NFATC/fisiologia , Neurônios/fisiologia , Percepção Espacial/fisiologia , Análise de Variância , Animais , Western Blotting , Técnicas de Cultura de Células , Condicionamento Psicológico/fisiologia , Primers do DNA/genética , Potenciais Evocados/fisiologia , Imuno-Histoquímica , Luciferases , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Knockout , Fatores de Transcrição NFATC/deficiência , Reação em Cadeia da Polimerase Via Transcriptase Reversa
4.
Nat Neurosci ; 27(8): 1545-1554, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38849524

RESUMO

In the mouse embryonic forebrain, developmentally distinct oligodendrocyte progenitor cell populations and their progeny, oligodendrocytes, emerge from three distinct regions in a spatiotemporal gradient from ventral to dorsal. However, the functional importance of this oligodendrocyte developmental heterogeneity is unknown. Using a genetic strategy to ablate dorsally derived oligodendrocyte lineage cells (OLCs), we show here that the areas in which dorsally derived OLCs normally reside in the adult central nervous system become populated and myelinated by OLCs of ventral origin. These ectopic oligodendrocytes (eOLs) have a distinctive gene expression profile as well as subtle myelination abnormalities. The failure of eOLs to fully assume the role of the original dorsally derived cells results in locomotor and cognitive deficits in the adult animal. This study reveals the importance of developmental heterogeneity within the oligodendrocyte lineage and its importance for homeostatic brain function.


Assuntos
Encéfalo , Linhagem da Célula , Oligodendroglia , Animais , Oligodendroglia/fisiologia , Camundongos , Encéfalo/citologia , Encéfalo/embriologia , Linhagem da Célula/fisiologia , Diferenciação Celular/fisiologia , Camundongos Transgênicos , Bainha de Mielina/metabolismo , Bainha de Mielina/fisiologia
5.
J Neurosci ; 32(40): 13956-70, 2012 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-23035104

RESUMO

Following spinal trauma, the limited physiological axonal sprouting that contributes to partial recovery of function is dependent upon the intrinsic properties of neurons as well as the inhibitory glial environment. The transcription factor p53 is involved in DNA repair, cell cycle, cell survival, and axonal outgrowth, suggesting p53 as key modifier of axonal and glial responses influencing functional recovery following spinal injury. Indeed, in a spinal cord dorsal hemisection injury model, we observed a significant impairment in locomotor recovery in p53(-/-) versus wild-type mice. p53(-/-) spinal cords showed an increased number of activated microglia/macrophages and a larger scar at the lesion site. Loss- and gain-of-function experiments suggested p53 as a direct regulator of microglia/macrophages proliferation. At the axonal level, p53(-/-) mice showed a more pronounced dieback of the corticospinal tract (CST) and a decreased sprouting capacity of both CST and spinal serotoninergic fibers. In vivo expression of p53 in the sensorimotor cortex rescued and enhanced the sprouting potential of the CST in p53(-/-) mice, while, similarly, p53 expression in p53(-/-) cultured cortical neurons rescued a defect in neurite outgrowth, suggesting a direct role for p53 in regulating the intrinsic sprouting ability of CNS neurons. In conclusion, we show that p53 plays an important regulatory role at both extrinsic and intrinsic levels affecting the recovery of motor function following spinal cord injury. Therefore, we propose p53 as a novel potential multilevel therapeutic target for spinal cord injury.


Assuntos
Locomoção/fisiologia , Neurônios/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Regeneração da Medula Espinal/fisiologia , Proteína Supressora de Tumor p53/fisiologia , Animais , Células Cultivadas , Cicatriz/patologia , Cordotomia , Comportamento Exploratório/fisiologia , Genes p53 , Temperatura Alta , Coxeadura Animal/etiologia , Coxeadura Animal/fisiopatologia , Ativação de Macrófagos , Masculino , Camundongos , Camundongos Knockout , Microglia/patologia , Plasticidade Neuronal/fisiologia , Tratos Piramidais/patologia , Recuperação de Função Fisiológica , Degeneração Retrógrada , Limiar Sensorial , Neurônios Serotoninérgicos/fisiologia , Traumatismos da Medula Espinal/genética , Regeneração da Medula Espinal/genética , Proteína Supressora de Tumor p53/deficiência
6.
Nat Commun ; 11(1): 5860, 2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-33203872

RESUMO

Mature oligodendrocytes (MOLs) show transcriptional heterogeneity, the functional consequences of which are unclear. MOL heterogeneity might correlate with the local environment or their interactions with different neuron types. Here, we show that distinct MOL populations have spatial preference in the mammalian central nervous system (CNS). We found that MOL type 2 (MOL2) is enriched in the spinal cord when compared to the brain, while MOL types 5 and 6 (MOL5/6) increase their contribution to the OL lineage with age in all analyzed regions. MOL2 and MOL5/6 also have distinct spatial preference in the spinal cord regions where motor and sensory tracts run. OL progenitor cells (OPCs) are not specified into distinct MOL populations during development, excluding a major contribution of OPC intrinsic mechanisms determining MOL heterogeneity. In disease, MOL2 and MOL5/6 present different susceptibility during the chronic phase following traumatic spinal cord injury. Our results demonstrate that the distinct MOL populations have different spatial preference and different responses to disease.


Assuntos
Oligodendroglia/citologia , Oligodendroglia/patologia , Traumatismos da Medula Espinal/fisiopatologia , Animais , Axônios/patologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Biomarcadores/metabolismo , Linhagem da Célula , Corpo Caloso/citologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Perfilação da Expressão Gênica , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Knockout , Camundongos Transgênicos , Oligodendroglia/fisiologia , Análise de Célula Única , Medula Espinal/citologia
7.
Cell Stem Cell ; 24(5): 677-679, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31051128

RESUMO

In this issue of Cell Stem Cell, Weng et al. (2019) characterize a progenitor population that precedes oligodendrocyte progenitor cells (OPCs). The authors identified Zfp36l1 as a key regulator of the cell fate switch between oligodendrocytes and astrocytes in neural progenitors, and thereby an important regulator of cellular processes such as myelination and gliomagenesis.


Assuntos
Células Precursoras de Oligodendrócitos , Transcriptoma , Astrócitos , Diferenciação Celular , Oligodendroglia
8.
Nat Med ; 24(12): 1837-1844, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30420755

RESUMO

Multiple sclerosis (MS) is characterized by an immune system attack targeting myelin, which is produced by oligodendrocytes (OLs). We performed single-cell transcriptomic analysis of OL lineage cells from the spinal cord of mice induced with experimental autoimmune encephalomyelitis (EAE), which mimics several aspects of MS. We found unique OLs and OL precursor cells (OPCs) in EAE and uncovered several genes specifically alternatively spliced in these cells. Surprisingly, EAE-specific OL lineage populations expressed genes involved in antigen processing and presentation via major histocompatibility complex class I and II (MHC-I and -II), and in immunoprotection, suggesting alternative functions of these cells in a disease context. Importantly, we found that disease-specific oligodendroglia are also present in human MS brains and that a substantial number of genes known to be susceptibility genes for MS, so far mainly associated with immune cells, are expressed in the OL lineage cells. Finally, we demonstrate that OPCs can phagocytose and that MHC-II-expressing OPCs can activate memory and effector CD4-positive T cells. Our results suggest that OLs and OPCs are not passive targets but instead active immunomodulators in MS. The disease-specific OL lineage cells, for which we identify several biomarkers, may represent novel direct targets for immunomodulatory therapeutic approaches in MS.


Assuntos
Linhagem da Célula/genética , Sistema Imunitário , Esclerose Múltipla/genética , Transcriptoma/genética , Processamento Alternativo/genética , Animais , Apresentação de Antígeno/genética , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/fisiopatologia , Regulação da Expressão Gênica/genética , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Camundongos , Esclerose Múltipla/fisiopatologia , Bainha de Mielina/genética , Células Precursoras de Oligodendrócitos/metabolismo , Células Precursoras de Oligodendrócitos/patologia , Oligodendroglia/metabolismo , Análise de Célula Única
9.
EBioMedicine ; 13: 55-65, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27818039

RESUMO

Stem cells have a high therapeutic potential for the treatment of spinal cord injury (SCI). We have shown previously that endogenous stem cell potential is confined to ependymal cells in the adult spinal cord which could be targeted for non-invasive SCI therapy. However, ependymal cells are an understudied cell population. Taking advantage of transgenic lines, we characterize the appearance and potential of ependymal cells during development. We show that spinal cord stem cell potential in vitro is contained within these cells by birth. Moreover, juvenile cultures generate more neurospheres and more oligodendrocytes than adult ones. Interestingly, juvenile ependymal cells in vivo contribute to glial scar formation after severe but not mild SCI, due to a more effective sealing of the lesion by other glial cells. This study highlights the importance of the age-dependent potential of stem cells and post-SCI environment in order to utilize ependymal cell's regenerative potential.


Assuntos
Diferenciação Celular , Epêndima/citologia , Células-Tronco Neurais/citologia , Regeneração , Traumatismos da Medula Espinal/patologia , Animais , Autorrenovação Celular , Células Cultivadas , Modelos Animais de Doenças , Genes Reporter , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Microglia/imunologia , Microglia/metabolismo , Células-Tronco Neurais/metabolismo , Medula Espinal/citologia , Medula Espinal/embriologia , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/terapia
10.
Science ; 352(6291): 1326-1329, 2016 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-27284195

RESUMO

Oligodendrocytes have been considered as a functionally homogeneous population in the central nervous system (CNS). We performed single-cell RNA sequencing on 5072 cells of the oligodendrocyte lineage from 10 regions of the mouse juvenile and adult CNS. Thirteen distinct populations were identified, 12 of which represent a continuum from Pdgfra(+) oligodendrocyte precursor cells (OPCs) to distinct mature oligodendrocytes. Initial stages of differentiation were similar across the juvenile CNS, whereas subsets of mature oligodendrocytes were enriched in specific regions in the adult brain. Newly formed oligodendrocytes were detected in the adult CNS and were responsive to complex motor learning. A second Pdgfra(+) population, distinct from OPCs, was found along vessels. Our study reveals the dynamics of oligodendrocyte differentiation and maturation, uncoupling them at a transcriptional level and highlighting oligodendrocyte heterogeneity in the CNS.


Assuntos
Encéfalo/crescimento & desenvolvimento , Neurogênese , Oligodendroglia/citologia , Animais , Antígenos/genética , Antígenos/metabolismo , Biomarcadores/metabolismo , Encéfalo/citologia , Linhagem da Célula , Células Cultivadas , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Aprendizagem/fisiologia , Camundongos , Atividade Motora/fisiologia , Bainha de Mielina/genética , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Proteoglicanas/genética , Proteoglicanas/metabolismo , RNA Mensageiro/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Análise de Sequência de RNA , Análise de Célula Única
11.
Neurosci Lett ; 580: 52-5, 2014 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-25102325

RESUMO

The evolutionarily conserved insulin/IGF-1 signaling pathway has pleiotropic effects on various cellular processes. Hypomorphic alleles of the insulin/IGF-1 receptor enhance catabolic processes as well as stress resistance, which ultimately lead to lifespan extension in invertebrates. Moreover, decreased insulin/IGF-1 signaling promotes the maintenance of protein quality control and suppresses the onset of cellular toxicity caused by aggregate-prone proteins. As loss of protein homeostasis is a feature of many sporadic and inherited forms of neurodegenerative disorders, the pharmacological inhibition of the IGF-1 receptor represents a promising potential therapeutic strategy for currently untreatable neurodegenerative disorders. However, additional studies are required to determine whether this approach is suitable to delay pathology in clinically relevant models of neurodegenerative disorders. Here we show that, in a mouse model of Huntington's disease, heterozygous knockout of the Igf1r does not prevent premature lethality of mice expressing a short fragment of the mutant human huntingtin. Moreover, Igf1r haploinsufficiency does not suppress the formation of huntingtin-containing aggregates. Thus, partial genetic manipulation of the insulin/IGF-1 signaling pathway does not seem sufficient to counteract protein toxicity and extend animal survival.


Assuntos
Doença de Huntington/patologia , Proteínas do Tecido Nervoso/genética , Receptor IGF Tipo 1/genética , Animais , Glutamina/análogos & derivados , Glutamina/metabolismo , Heterozigoto , Humanos , Proteína Huntingtina , Doença de Huntington/genética , Camundongos Knockout , Proteínas do Tecido Nervoso/metabolismo , Peptídeos/metabolismo , Agregados Proteicos , Receptor IGF Tipo 1/metabolismo
12.
Mol Neurobiol ; 46(2): 227-41, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22717989

RESUMO

One only needs to see a salamander regrowing a lost limb to become fascinated by regeneration. However, the lack of robust axonal regeneration models for which good cellular and molecular tools exist has hampered progress in the field. Nevertheless, the nervous system has been revealed to be an excellent model to investigate regeneration. There are conspicuous differences in neuroregeneration capacity between amphibia and warm-blooded animals, as well as between the central and the peripheral nervous systems in mammals. Exploration of such discrepancies led to significant discoveries on the basic tenets of neuroregeneration in the last two decades, identifying several positive and negative regulators of axonal regeneration. Implications of these findings to the comprehension of mammalian regeneration and to the development of spinal cord injury therapies are also addressed.


Assuntos
Sistema Nervoso Central/fisiologia , Regeneração Nervosa/fisiologia , Sistema Nervoso Periférico/fisiologia , Animais , Fenômenos Eletrofisiológicos , Humanos , Traumatismos da Medula Espinal/fisiopatologia
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