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1.
Mol Neurobiol ; 57(12): 5263-5275, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32869183

RESUMO

Similar to its predecessors, coronavirus disease 2019 (COVID-19) exhibits neurotrophic properties, which lead to progression of neurologic sequelae. Besides direct viral invasion to the central nervous system (CNS), indirect CNS involvement through viral-mediated immune response is plausible. Aberrant immune pathways such as extreme release of cytokines (cytokine storm), autoimmunity mediated by cross-reactivity between CNS components and viral particles, and microglial activation propagate CNS damage in these patients. Here, we review the currently available evidence to discuss the plausible immunologic pathways that may contribute to the development of COVID-19 neurological complications, namely Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis, Guillain-Barre syndrome, seizure, and brainstem involvement.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Doenças do Sistema Nervoso/etiologia , Pandemias , Pneumonia Viral/complicações , Animais , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Tronco Encefálico/fisiopatologia , Tronco Encefálico/virologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Efeito Citopatogênico Viral , Surtos de Doenças , Síndrome de Guillain-Barré/etiologia , Síndrome de Guillain-Barré/imunologia , Humanos , Camundongos , Esclerose Múltipla/etiologia , Esclerose Múltipla/imunologia , Proteínas do Tecido Nervoso/fisiologia , Doenças do Sistema Nervoso/imunologia , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/imunologia , Neuroglia/patologia , Neuroglia/virologia , Neurônios/patologia , Neurônios/virologia , Peptidil Dipeptidase A/fisiologia , Pneumonia Viral/imunologia , Receptores Virais/fisiologia , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/fisiopatologia , Convulsões/etiologia , Convulsões/imunologia , Síndrome Respiratória Aguda Grave/complicações , Síndrome Respiratória Aguda Grave/epidemiologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/imunologia
2.
Nat Commun ; 11(1): 4491, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901033

RESUMO

The functionality of the nervous system requires transmission of information along axons with high speed and precision. Conductance velocity depends on axonal diameter whereas signaling precision requires a block of electrical crosstalk between axons, known as ephaptic coupling. Here, we use the peripheral nervous system of Drosophila larvae to determine how glia regulates axonal properties. We show that wrapping glial differentiation depends on gap junctions and FGF-signaling. Abnormal glial differentiation affects axonal diameter and conductance velocity and causes mild behavioral phenotypes that can be rescued by a sphingosine-rich diet. Ablation of wrapping glia does not further impair axonal diameter and conductance velocity but causes a prominent locomotion phenotype that cannot be rescued by sphingosine. Moreover, optogenetically evoked locomotor patterns do not depend on conductance speed but require the presence of wrapping glial processes. In conclusion, our data indicate that wrapping glia modulates both speed and precision of neuronal signaling.


Assuntos
Drosophila melanogaster/fisiologia , Animais , Animais Geneticamente Modificados , Axônios/fisiologia , Diferenciação Celular , Proteínas de Drosophila/genética , Proteínas de Drosophila/fisiologia , Drosophila melanogaster/citologia , Drosophila melanogaster/genética , Larva/citologia , Larva/fisiologia , Locomoção/fisiologia , Modelos Neurológicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Neuroglia/citologia , Neuroglia/fisiologia , Optogenética , Sistema Nervoso Periférico/citologia , Sistema Nervoso Periférico/fisiologia , Fenótipo , Receptores de Fatores de Crescimento de Fibroblastos/fisiologia , Transdução de Sinais
3.
Chem Biol Interact ; 330: 109251, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32888910

RESUMO

Cisplatin induces acute renal failure in humans and mice.Tubular apoptosis, necrosis and inflammation are the primary pathogenesis of cisplatin-induced acute kidney injury(AKI). We previously reported that the depletion of Numb from proximal tubules exacerbates tubular cells apoptosis in cisplatin-induced AKI, however, the role of Numb in tubular necrosis and renal inflammation in cisplatin-induced AKI remains unclear. A mouse model of AKI was produced by cisplatin intraperitoneally injection in mice from proximal tubule-specific depletion of Numb (PT-Nb-KO) and their wild-type littermates (PT-Nb-WT) respectively. Renal Numb expression was determined by Western blotting. Renal morphological damage was examined by hematoxylin and eosin staining (H&E staining). Tubular necrosis was evaluated by histological study and the protein level of renal Mixed lineage kinase domain-like protein (MLKL) which is a molecular marker of necrosis. Leukocyte infiltration and pro-inflammatory cytokines was determined by immunostaining and quantitative real-time PCR (qRT-PCR) respectively.The protein level of Numb was dramatically decreased in kidneys of PT-Nb-KO mice compared with PT-Nb-WT mice. After cisplatin injection, a significant increase of tubular injury score and the protein level of renal MLKL were detected in PT-Nb-KO mice compared with those in PT-Nb-WT. In addition, the number of F4/80-positve and CD3-positive cells, markers for macrophages and neutraphils respectively, showed significantly increased in kidneys from PT-Nb-KO mice compared with those in PT-Nb-WT mice. Consistently, the gene expression of pro-inflammatory cytokines including TNF-α and MCP-1 in the kidneys was higher in PT-Nb-KO mice than those in PT-Nb-WT mice. Numb play additional protective role in cisplatin-induced AKI through ameliorating tubular necrosis and renal inflammation besides attenuating cisplatin-induced tubular apoptosis.


Assuntos
Lesão Renal Aguda/patologia , Cisplatino/efeitos adversos , Inflamação/prevenção & controle , Proteínas de Membrana/fisiologia , Necrose/prevenção & controle , Proteínas do Tecido Nervoso/fisiologia , Animais , Contagem de Células , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamação/etiologia , Túbulos Renais Proximais/patologia , Mastócitos , Proteínas de Membrana/deficiência , Camundongos , Camundongos Knockout , Necrose/etiologia , Proteínas do Tecido Nervoso/deficiência , Neutrófilos , Proteínas Quinases/metabolismo
4.
Viruses ; 12(9)2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32911874

RESUMO

Since the global outbreak of SARS-CoV-2 (COVID-19), infections of diverse human organs along with multiple symptoms continue to be reported. However, the susceptibility of the brain to SARS-CoV-2, and the mechanisms underlying neurological infection are still elusive. Here, we utilized human embryonic stem cell-derived brain organoids and monolayer cortical neurons to investigate infection of brain with pseudotyped SARS-CoV-2 viral particles. Spike-containing SARS-CoV-2 pseudovirus infected neural layers within brain organoids. The expression of ACE2, a host cell receptor for SARS-CoV-2, was sustained during the development of brain organoids, especially in the somas of mature neurons, while remaining rare in neural stem cells. However, pseudotyped SARS-CoV-2 was observed in the axon of neurons, which lack ACE2. Neural infectivity of SARS-CoV-2 pseudovirus did not increase in proportion to viral load, but only 10% of neurons were infected. Our findings demonstrate that brain organoids provide a useful model for investigating SARS-CoV-2 entry into the human brain and elucidating the susceptibility of the brain to SARS-CoV-2.


Assuntos
Betacoronavirus/fisiologia , Neurônios/virologia , Organoides/virologia , Prosencéfalo/virologia , Glicoproteína da Espícula de Coronavírus/fisiologia , Axônios/enzimologia , Diferenciação Celular , Células Cultivadas , Córtex Cerebral/citologia , Células-Tronco Embrionárias/virologia , Células HEK293 , Humanos , Proteínas do Tecido Nervoso/fisiologia , Células-Tronco Neurais/enzimologia , Células-Tronco Neurais/virologia , Neurônios/enzimologia , Peptidil Dipeptidase A/fisiologia , Prosencéfalo/citologia , Receptores Virais/fisiologia , Carga Viral , Tropismo Viral , Internalização do Vírus
5.
Am J Physiol Endocrinol Metab ; 319(2): E354-E362, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32603260

RESUMO

Browning of white adipose tissue (WAT) has been shown to reduce obesity and obesity-related complications, suggesting that factors that promote WAT browning may have applications in the development of therapeutic strategies for treating obesity. Here, we show that ablation of spinophilin (SPL), a ubiquitously expressed, multidomain scaffolding protein, increases metabolism and improves energy balance. Male and female SPL knockout (KO) and wild-type (WT) littermate controls were fed a chow diet or a high-fat diet (HFD). Body weight, hepatic steatosis, glucose and insulin tolerance, physical activity, and expression of browning genes in adipose tissues were measured and compared. Male SPL knockout (KO) mice fed a chow diet were significantly leaner, had lower body weights, and exhibited better glucose tolerance and insulin sensitivity than wild-type (WT) littermate controls. When fed an HFD, SPL KO mice were protected from increased body fat, weight gain, hepatic steatosis, hyperinsulinemia, and insulin resistance. Physical activity of SPL KO mice was markedly increased compared with WT controls. Furthermore, expression of the brown adipocyte marker, uncoupling protein-1 (UCP-1), and the mitochondrial activity markers, cd137 and c-idea, were significantly increased in visceral WAT (vWAT) of SPL KO mice, suggesting that SPL knockout protected the mice from HFD-induced obesity and its metabolic complications, at least in part, by promoting the browning of white adipocytes in vWAT. Our data identify a critical role of SPL in regulating glucose homeostasis, obesity, and adipocyte browning. These results suggest SPL may serve as a drug target for obesity and diabetes.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina/fisiologia , Proteínas dos Microfilamentos/deficiência , Proteínas do Tecido Nervoso/deficiência , Obesidade/prevenção & controle , Adiponectina/sangue , Tecido Adiposo Marrom/fisiopatologia , Tecido Adiposo Branco/fisiopatologia , Animais , Metabolismo Energético , Fígado Gorduroso/fisiopatologia , Fígado Gorduroso/prevenção & controle , Feminino , Leptina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas dos Microfilamentos/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Obesidade/etiologia , Obesidade/fisiopatologia , Esforço Físico/fisiologia
6.
Nat Neurosci ; 23(6): 707-717, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32451484

RESUMO

Neuronal activation induces rapid transcription of immediate early genes (IEGs) and longer-term chromatin remodeling around secondary response genes (SRGs). Here, we use high-resolution chromosome-conformation-capture carbon-copy sequencing (5C-seq) to elucidate the extent to which long-range chromatin loops are altered during short- and long-term changes in neural activity. We find that more than 10% of loops surrounding select IEGs, SRGs, and synaptic genes are induced de novo during cortical neuron activation. IEGs Fos and Arc connect to activity-dependent enhancers via singular short-range loops that form within 20 min after stimulation, prior to peak messenger RNA levels. By contrast, the SRG Bdnf engages in both pre-existing and activity-inducible loops that form within 1-6 h. We also show that common single-nucleotide variants that are associated with autism and schizophrenia are colocalized with distinct classes of activity-dependent, looped enhancers. Our data link architectural complexity to transcriptional kinetics and reveal the rapid timescale by which higher-order chromatin architecture reconfigures during neuronal stimulation.


Assuntos
Montagem e Desmontagem da Cromatina/fisiologia , Expressão Gênica/fisiologia , Genoma/genética , Neurônios/fisiologia , Animais , Bicuculina/farmacologia , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Montagem e Desmontagem da Cromatina/genética , Proteínas do Citoesqueleto/fisiologia , Genoma/efeitos dos fármacos , Humanos , Camundongos , Proteínas do Tecido Nervoso/fisiologia , Neurônios/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/fisiologia , Tetrodotoxina/farmacologia , Fatores de Tempo
7.
J Neurosci ; 40(11): 2246-2258, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32001613

RESUMO

The ependyma of the adult spinal cord is a latent stem cell niche that is reactivated by spinal cord injury contributing new cells to the glial scar. The cellular events taking place in the early stages of the reaction of the ependyma to injury remain little understood. Ependymal cells are functionally heterogeneous with a mitotically active subpopulation lining the lateral domains of the central canal (CC) that are coupled via gap junctions. Gap junctions and connexin hemichannels are key regulators of the biology of neural progenitors during development and in adult neurogenic niches. Thus, we hypothesized that communication via connexins in the CC is developmentally regulated and may play a part in the reactivation of this latent stem cell niche after injury. To test these possibilities, we combined patch-clamp recordings of ependymal cells with immunohistochemistry for various connexins in the neonatal and the adult (P > 90) normal and injured spinal cord of male and female mice. We find that coupling among ependymal cells is downregulated as postnatal development proceeds but increases after injury, resembling the immature CC. The increase in gap junction coupling in the adult CC was paralleled by upregulation of connexin 26, which correlated with the resumption of proliferation and a reduction of connexin hemichannel activity. Connexin blockade reduced the injury-induced proliferation of ependymal cells. Our findings suggest that connexins are involved in the early reaction of ependymal cells to injury, representing a potential target to improve the contribution of the CC stem cell niche to repair.SIGNIFICANCE STATEMENT Ependymal cells in the adult spinal cord are latent progenitors that react to injury to support some degree of endogenous repair. Understanding the mechanisms by which these progenitor-like cells are regulated in the aftermath of spinal cord injury is critical to design future manipulations aimed at improving healing and functional recovery. Gap junctions and connexin hemichannels are key regulators of the biology of neural progenitors during development and in adult neurogenic niches. We find here that connexin signaling in the ependyma changes after injury of the adult spinal cord, functionally resembling the immature active-stem cell niche of neonatal animals. Our findings suggest that connexins in ependymal cells are potential targets to improve self-repair of the spinal cord.


Assuntos
Conexinas/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Nicho de Células-Tronco/fisiologia , Fatores Etários , Sequência de Aminoácidos , Animais , Animais Recém-Nascidos , Membrana Celular/fisiologia , Permeabilidade da Membrana Celular , Conexinas/antagonistas & inibidores , Epêndima/citologia , Epêndima/crescimento & desenvolvimento , Feminino , Corantes Fluorescentes/farmacocinética , Junções Comunicantes/fisiologia , Hidrogéis , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/antagonistas & inibidores , Técnicas de Patch-Clamp , Peptídeos/química , Peptídeos/farmacologia , Poloxâmero/farmacologia , Distribuição Aleatória
8.
Neuron ; 106(2): 246-255.e6, 2020 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-32097629

RESUMO

Genes mutated in human neuronal migration disorders encode tubulin proteins and a variety of tubulin-binding and -regulating proteins, but it is very poorly understood how these proteins function together to coordinate migration. Additionally, the way in which regional differences in neocortical migration are controlled is completely unknown. Here we describe a new syndrome with remarkably region-specific effects on neuronal migration in the posterior cortex, reflecting de novo variants in CEP85L. We show that CEP85L is required cell autonomously in vivo and in vitro for migration, that it localizes to the maternal centriole, and that it forms a complex with many other proteins required for migration, including CDK5, LIS1, NDE1, KIF2A, and DYNC1H1. Loss of CEP85L disrupts CDK5 localization and activation, leading to centrosome disorganization and disrupted microtubule cytoskeleton organization. Together, our findings suggest that CEP85L highlights a complex that controls CDK5 activity to promote neuronal migration.


Assuntos
Movimento Celular , Quinase 5 Dependente de Ciclina/genética , Proteínas do Citoesqueleto/genética , Lisencefalia/genética , Lisencefalia/patologia , Neocórtex/patologia , Neurônios/patologia , Proteínas de Fusão Oncogênica/genética , Centríolos/genética , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Microtúbulos/genética , Microtúbulos/ultraestrutura , Proteínas do Tecido Nervoso/fisiologia , Adulto Jovem
9.
Metabolism ; 105: 154189, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32105664

RESUMO

BACKGROUND: Sprouty (SPRY) proteins play critical roles in controlling cell proliferation, differentiation, and survival by inhibiting receptor tyrosine kinase (RTK)-mediated extracellular signal-regulated kinase (ERK) signaling. Recent studies have demonstrated that SPRY4 negatively regulates angiogenesis and tumor growth. However, whether SPRY4 regulates osteogenic and/or adipogenic differentiation of mesenchymal stem cells remains to be explored. RESULTS: In this study, we investigated the expression pattern of Spry4 and found that its expression was regulated during the differentiation of mouse marrow stromal progenitor cells and increased in the metaphysis of ovariectomized mice. In vitro loss-of-function and gain-of-function studies demonstrated that SPRY4 inhibited osteogenic differentiation and stimulated adipogenic differentiation of progenitor cells. In vivo experiments showed that silencing of Spry4 in the marrow of C57BL/6 mice blocked fat accumulation and promoted osteoblast differentiation in ovariectomized mice. Mechanistic investigations revealed the inhibitory effect of SPRY4 on canonical wingless-type MMTV integration site (Wnt) signaling and ERK pathway. ERK1/2 was shown to interact with low-density lipoprotein receptor-related protein 6 (LRP6) and activate the canonical Wnt signaling pathway. Inactivation of Wnt signaling attenuated the inhibition of adipogenic differentiation and stimulation of osteogenic differentiation by Spry4 small interfering RNA (siRNA). Finally, promoter study revealed that ß-catenin transcriptionally inhibited the expression of Spry4. CONCLUSIONS: Our study for the first time suggests that a novel SPRY4-ERK1/2-Wnt/ß-catenin regulatory loop exists in marrow stromal progenitor cells and plays a key role in cell fate determination. It also highlights the potential of SPRY4 as a novel therapeutic target for the treatment of metabolic bone disorders such as osteoporosis.


Assuntos
Adipogenia/genética , Adipogenia/fisiologia , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/fisiologia , Células-Tronco Mesenquimais/fisiologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Osteogênese/genética , Osteogênese/fisiologia , Via de Sinalização Wnt/genética , Via de Sinalização Wnt/fisiologia , beta Catenina/genética , beta Catenina/fisiologia , Animais , Medula Óssea/metabolismo , Feminino , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Ovariectomia , RNA Interferente Pequeno/farmacologia
10.
Neuron ; 105(6): 1007-1017.e5, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-31974009

RESUMO

LRRTM4 is a transsynaptic adhesion protein regulating glutamatergic synapse assembly on dendrites of central neurons. In the mouse retina, we find that LRRTM4 is enriched at GABAergic synapses on axon terminals of rod bipolar cells (RBCs). Knockout of LRRTM4 reduces RBC axonal GABAA and GABAC receptor clustering and disrupts presynaptic inhibition onto RBC terminals. LRRTM4 removal also perturbs the stereotyped output synapse arrangement at RBC terminals. Synaptic ribbons are normally apposed to two distinct postsynaptic "dyad" partners, but in the absence of LRRTM4, "monad" and "triad" arrangements are also formed. RBCs from retinas deficient in GABA release also demonstrate dyad mis-arrangements but maintain LRRTM4 expression, suggesting that defects in dyad organization in the LRRTM4 knockout could originate from reduced GABA receptor function. LRRTM4 is thus a key synapse organizing molecule at RBC terminals, where it regulates function of GABAergic synapses and assembly of RBC synaptic dyads.


Assuntos
Proteínas de Membrana/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Inibição Neural/fisiologia , Terminações Pré-Sinápticas/fisiologia , Células Bipolares da Retina/fisiologia , Animais , Feminino , Masculino , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Receptores de GABA/metabolismo , Receptores de GABA/fisiologia , Retina/metabolismo , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/genética , Ácido gama-Aminobutírico/metabolismo
11.
J Neurosci ; 40(1): 12-21, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31896560

RESUMO

Over the last 50 years, the concept of stress has evolved significantly, and our understanding of the underlying neurobiology has expanded dramatically. Rather than consider stress biology to be relevant only under unusual and threatening conditions, we conceive of it as an ongoing, adaptive process of assessing the environment, coping with it, and enabling the individual to anticipate and deal with future challenges. Though much remains to be discovered, the fundamental neurocircuitry that underlies these processes has been broadly delineated, key molecular players have been identified, and the impact of this system on neuroplasticity has been well established. More recently, we have come to appreciate the critical interaction between the brain and the rest of the body as it pertains to stress responsiveness. Importantly, this system can become overloaded due to ongoing environmental demands on the individual, be they physical, physiological, or psychosocial. The impact of this overload is deleterious to brain health, and it results in vulnerability to a range of brain disorders, including major depression and cognitive deficits. Thus, stress biology is one of the best understood systems in affective neuroscience and is an ideal target for addressing the pathophysiology of many brain-related diseases. The story we present began with the discovery of glucocorticoid receptors in hippocampus and has extended to other brain regions in both animal models and the human brain with the further discovery of structural and functional adaptive plasticity in response to stressful and other experiences.


Assuntos
Encéfalo/fisiologia , Glucocorticoides/fisiologia , Transtornos do Humor/fisiopatologia , Estresse Fisiológico/fisiologia , Estresse Psicológico/fisiopatologia , Adaptação Fisiológica/fisiologia , Animais , Endocanabinoides/fisiologia , Epigênese Genética , Retroalimentação Fisiológica , Fator 2 de Crescimento de Fibroblastos/fisiologia , Fator 2 de Crescimento de Fibroblastos/uso terapêutico , Regulação da Expressão Gênica/fisiologia , Hormônios/fisiologia , Humanos , Sistema Hipotálamo-Hipofisário/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Acontecimentos que Mudam a Vida , Modelos Neurológicos , Modelos Psicológicos , Transtornos do Humor/etiologia , Transtornos do Humor/psicologia , Proteínas do Tecido Nervoso/fisiologia , Plasticidade Neuronal , Sistema Hipófise-Suprarrenal/fisiologia , Psicofisiologia , Receptores de Superfície Celular/fisiologia , Determinantes Sociais da Saúde
12.
J Neurosci ; 40(7): 1405-1426, 2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-31915257

RESUMO

BDNF signaling via its transmembrane receptor TrkB has an important role in neuronal survival, differentiation, and synaptic plasticity. Remarkably, BDNF is capable of modulating its own expression levels in neurons, forming a transcriptional positive feedback loop. In the current study, we have investigated this phenomenon in primary cultures of rat cortical neurons using overexpression of dominant-negative forms of several transcription factors, including CREB, ATF2, C/EBP, USF, and NFAT. We show that CREB family transcription factors, together with the coactivator CBP/p300, but not the CRTC family, are the main regulators of rat BDNF gene expression after TrkB signaling. CREB family transcription factors are required for the early induction of all the major BDNF transcripts, whereas CREB itself directly binds only to BDNF promoter IV, is phosphorylated in response to BDNF-TrkB signaling, and activates transcription from BDNF promoter IV by recruiting CBP. Our complementary reporter assays with BDNF promoter constructs indicate that the regulation of BDNF by CREB family after BDNF-TrkB signaling is generally conserved between rat and human. However, we demonstrate that a nonconserved functional cAMP-responsive element in BDNF promoter IXa in humans renders the human promoter responsive to BDNF-TrkB-CREB signaling, whereas the rat ortholog is unresponsive. Finally, we show that extensive BDNF transcriptional autoregulation, encompassing all major BDNF transcripts, occurs also in vivo in the adult rat hippocampus during BDNF-induced LTP. Collectively, these results improve the understanding of the intricate mechanism of BDNF transcriptional autoregulation.SIGNIFICANCE STATEMENT Deeper understanding of stimulus-specific regulation of BDNF gene expression is essential to precisely adjust BDNF levels that are dysregulated in various neurological disorders. Here, we have elucidated the molecular mechanisms behind TrkB signaling-dependent BDNF mRNA induction and show that CREB family transcription factors are the main regulators of BDNF gene expression after TrkB signaling. Our results suggest that BDNF-TrkB signaling may induce BDNF gene expression in a distinct manner compared with neuronal activity. Moreover, our data suggest the existence of a stimulus-specific distal enhancer modulating BDNF gene expression.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/fisiologia , Fator Neurotrófico Derivado do Encéfalo/genética , Córtex Cerebral/citologia , Regulação da Expressão Gênica/genética , Hipocampo/citologia , Proteínas do Tecido Nervoso/fisiologia , Neurônios/metabolismo , Transdução de Sinais/fisiologia , Transcrição Genética/genética , Animais , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Células Cultivadas , Córtex Cerebral/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/fisiologia , Proteínas do Citoesqueleto/biossíntese , Proteínas do Citoesqueleto/genética , Retroalimentação Fisiológica , Feminino , Genes Dominantes , Genes Reporter , Genes Sintéticos , Hipocampo/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Regiões Promotoras Genéticas , Inibidores de Proteínas Quinases/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor trkB/fisiologia , Proteínas Recombinantes/farmacologia , Elementos de Resposta , Especificidade da Espécie , Transdução Genética
13.
J Neurosci ; 40(7): 1453-1482, 2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-31896673

RESUMO

During adult hippocampal neurogenesis, most newborn cells undergo apoptosis and are rapidly phagocytosed by resident microglia to prevent the spillover of intracellular contents. Here, we propose that phagocytosis is not merely passive corpse removal but has an active role in maintaining neurogenesis. First, we found that neurogenesis was disrupted in male and female mice chronically deficient for two phagocytosis pathways: the purinergic receptor P2Y12, and the tyrosine kinases of the TAM family Mer tyrosine kinase (MerTK)/Axl. In contrast, neurogenesis was transiently increased in mice in which MerTK expression was conditionally downregulated. Next, we performed a transcriptomic analysis of the changes induced by phagocytosis in microglia in vitro and identified genes involved in metabolism, chromatin remodeling, and neurogenesis-related functions. Finally, we discovered that the secretome of phagocytic microglia limits the production of new neurons both in vivo and in vitro Our data suggest that microglia act as a sensor of local cell death, modulating the balance between proliferation and survival in the neurogenic niche through the phagocytosis secretome, thereby supporting the long-term maintenance of adult hippocampal neurogenesis.SIGNIFICANCE STATEMENT Microglia are the brain professional phagocytes and, in the adult hippocampal neurogenic niche, they remove newborn cells naturally undergoing apoptosis. Here we show that phagocytosis of apoptotic cells triggers a coordinated transcriptional program that alters their secretome, limiting neurogenesis both in vivo and in vitro In addition, chronic phagocytosis disruption in mice deficient for receptors P2Y12 and MerTK/Axl reduces adult hippocampal neurogenesis. In contrast, inducible MerTK downregulation transiently increases neurogenesis, suggesting that microglial phagocytosis provides a negative feedback loop that is necessary for the long-term maintenance of adult hippocampal neurogenesis. Therefore, we speculate that the effects of promoting engulfment/degradation of cell debris may go beyond merely removing corpses to actively promoting regeneration in development, aging, and neurodegenerative diseases.


Assuntos
Hipocampo/citologia , Neurogênese/fisiologia , Neurônios/citologia , Fagocitose/fisiologia , Animais , Apoptose , Sinalização do Cálcio , Linhagem Celular Tumoral , Montagem e Desmontagem da Cromatina , Meios de Cultivo Condicionados , Retroalimentação Fisiológica , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Genes Reporter , Hipocampo/crescimento & desenvolvimento , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia , Regeneração Nervosa/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Receptores Purinérgicos P2Y12/fisiologia , Transcriptoma , c-Mer Tirosina Quinase/fisiologia
14.
J Neurosci ; 40(7): 1514-1526, 2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-31911459

RESUMO

The neurodevelopmental disorder Rett syndrome is caused by mutations in the gene Mecp2 Misexpression of the protein MECP2 is thought to contribute to neuropathology by causing dysregulation of plasticity. Female heterozygous Mecp2 mutants (Mecp2het ) failed to acquire a learned maternal retrieval behavior when exposed to pups, an effect linked to disruption of parvalbumin-expressing inhibitory interneurons (PV) in the auditory cortex. Nevertheless, how dysregulated PV networks affect the neural activity dynamics that underlie auditory cortical plasticity during early maternal experience is unknown. Here we show that maternal experience in WT adult female mice (WT) triggers suppression of PV auditory responses. We also observe concomitant disinhibition of auditory responses in deep-layer pyramidal neurons that is selective for behaviorally relevant pup vocalizations. These neurons further exhibit sharpened tuning for pup vocalizations following maternal experience. All of these neuronal changes are abolished in Mecp2het , suggesting that they are an essential component of maternal learning. This is further supported by our finding that genetic manipulation of GABAergic networks that restores accurate retrieval behavior in Mecp2het also restores maternal experience-dependent plasticity of PV. Our data are consistent with a growing body of evidence that cortical networks are particularly vulnerable to mutations of Mecp2 in PV neurons. Moreover, our work links, for the first time, impaired in vivo cortical plasticity in awake Mecp2 mutant animals to a natural, ethologically relevant behavior.SIGNIFICANCE STATEMENT Rett syndrome is a genetic disorder that includes language communication problems. Nearly all Rett syndrome is caused by mutations in the gene that produces the protein MECP2, which is important for changes in brain connectivity believed to underlie learning. We previously showed that female Mecp2 mutants fail to learn a simple maternal care behavior performed in response to their pups' distress cries. This impairment appeared to critically involve inhibitory neurons in the auditory cortex called parvalbumin neurons. Here we record from these neurons before and after maternal experience, and we show that they adapt their response to pup calls during maternal learning in nonmutants, but not in mutants. This adaptation is partially restored by a manipulation that improves learning.


Assuntos
Córtex Auditivo/fisiopatologia , Deficiências da Aprendizagem/fisiopatologia , Comportamento Materno/fisiologia , Proteína 2 de Ligação a Metil-CpG/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Plasticidade Neuronal/fisiologia , Estimulação Acústica , Animais , Animais Recém-Nascidos , Animais Lactentes , Córtex Auditivo/patologia , Feminino , Neurônios GABAérgicos/fisiologia , Glutamato Descarboxilase/deficiência , Glutamato Descarboxilase/fisiologia , Interneurônios/fisiologia , Deficiências da Aprendizagem/genética , Proteína 2 de Ligação a Metil-CpG/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Proteínas do Tecido Nervoso/deficiência , Técnicas de Patch-Clamp , Células Piramidais/fisiologia , Síndrome de Rett/genética , Análise de Célula Única , Vocalização Animal
15.
J Neurosci ; 40(7): 1581-1593, 2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-31915254

RESUMO

Alzheimer's disease (AD) is the most common neurodegenerative disorder, resulting in the progressive decline of cognitive function in patients. Familial forms of AD are tied to mutations in the amyloid precursor protein, but the cellular mechanisms that cause AD remain unclear. Inflammation and amyloidosis from amyloid ß (Aß) aggregates are implicated in neuron loss and cognitive decline. Inflammation activates the protein-tyrosine phosphatase 1B (PTP1B), and this could suppress many signaling pathways that activate glycogen synthase kinase 3ß (GSK3ß) implicated in neurodegeneration. However, the significance of PTP1B in AD pathology remains unclear. Here, we show that pharmacological inhibition of PTP1B with trodusquemine or selective ablation of PTP1B in neurons prevents hippocampal neuron loss and spatial memory deficits in a transgenic AD mouse model with Aß pathology (hAPP-J20 mice of both sexes). Intriguingly, while systemic inhibition of PTP1B reduced inflammation in the hippocampus, neuronal PTP1B ablation did not. These results dissociate inflammation from neuronal loss and cognitive decline and demonstrate that neuronal PTP1B hastens neurodegeneration and cognitive decline in this model of AD. The protective effect of PTP1B inhibition or ablation coincides with the restoration of GSK3ß inhibition. Neuronal ablation of PTP1B did not affect cerebral amyloid levels or plaque numbers, but reduced Aß plaque size in the hippocampus. In summary, our preclinical study suggests that targeting PTP1B may be a new strategy to intervene in the progression of AD.SIGNIFICANCE STATEMENT Familial forms of Alzheimer's disease (AD) are tied to mutations in the amyloid precursor protein, but the cellular mechanisms that cause AD remain unclear. Here, we used a mouse model expressing human amyloid precursor protein bearing two familial mutations and asked whether activation of a phosphatase PTP1B participates in the disease process. Systemic inhibition of this phosphatase using a selective inhibitor prevented cognitive decline, neuron loss in the hippocampus, and attenuated inflammation. Importantly, neuron-targeted ablation of PTP1B also prevented cognitive decline and neuron loss but did not reduce inflammation. Therefore, neuronal loss rather than inflammation was critical for AD progression in this mouse model, and that disease progression could be ameliorated by inhibition of PTP1B.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/fisiologia , Memória Espacial/fisiologia , Peptídeos beta-Amiloides/análise , Animais , Colestanos/farmacologia , Modelos Animais de Doenças , Feminino , Glicogênio Sintase Quinase 3 beta/fisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Humanos , Inflamação , Resistência à Insulina , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Proteínas do Tecido Nervoso/antagonistas & inibidores , Fragmentos de Peptídeos/análise , Placa Amiloide/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Memória Espacial/efeitos dos fármacos , Espermina/análogos & derivados , Espermina/farmacologia
16.
Am J Pathol ; 190(1): 176-189, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31676329

RESUMO

Nephronophthisis (NPHP), the leading genetic cause of end-stage renal failure in children and young adults, is a group of autosomal recessive diseases characterized by kidney-cyst degeneration and fibrosis for which no therapy is currently available. To date, mutations in >25 genes have been identified as causes of this disease that, in several cases, result in chronic DNA damage in kidney tubular cells. Among such mutations, those in the transcription factor-encoding GLIS2 cause NPHP type 7. Loss of function of mouse Glis2 causes senescence of kidney tubular cells. Senescent cells secrete proinflammatory molecules that induce progressive organ damage through several pathways, among which NF-κB signaling is prevalent. Herein, we show that the NF-κB signaling is active in Glis2 knockout kidney epithelial cells and that genetic inactivation of the toll-like receptor (TLR)/IL-1 receptor or pharmacologic elimination of senescent cells (senolytic therapy) reduces tubule damage, fibrosis, and apoptosis in the Glis2 mouse model of NPHP. Notably, in Glis2, Tlr2 double knockouts, senescence was also reduced and proliferation was increased, suggesting that loss of TLR2 activity improves the regenerative potential of tubular cells in Glis2 knockout kidneys. Our results further suggest that a combination of TLR/IL-1 receptor inhibition and senolytic therapy may delay the progression of kidney disease in NPHP type 7 and other forms of this disease.


Assuntos
Senescência Celular/imunologia , Modelos Animais de Doenças , Imunidade Inata/imunologia , Doenças Renais Císticas/patologia , Túbulos Renais/patologia , Fatores de Transcrição Kruppel-Like/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Animais , Apoptose , Doenças Renais Císticas/imunologia , Doenças Renais Císticas/metabolismo , Túbulos Renais/imunologia , Túbulos Renais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/fisiologia , Receptor 2 Toll-Like/fisiologia
17.
Exp Neurol ; 323: 113068, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31629859

RESUMO

The adult mammalian central nervous system (CNS) rarely recovers from injury. Myelin fragments contain axonal growth inhibitors that limit axonal regeneration, thus playing a major role in determining neural recovery. Nogo receptor-1 (NgR1) and its ligands are among the inhibitors that limit axonal regeneration. It has been previously shown that the endogenous protein, lateral olfactory tract usher substance (LOTUS), antagonizes NgR1-mediated signaling and accelerates neuronal plasticity after spinal cord injury and cerebral ischemia in mice. However, it remained unclear whether LOTUS-mediated reorganization of descending motor pathways in the adult brain is physiologically functional and contributes to functional recovery. Here, we generated LOTUS-overexpressing transgenic (LOTUS-Tg) rats to investigate the role of LOTUS in neuronal function after damage. After unilateral pyramidotomy, motor function in LOTUS-Tg rats recovered significantly compared to that in wild-type animals. In a retrograde tracing study, labeled axons spanning from the impaired side of the cervical spinal cord to the unlesioned hemisphere of the red nucleus and sensorimotor cortex were increased in LOTUS-Tg rats. Anterograde tracing from the unlesioned cortex also revealed enhanced ipsilateral connectivity to the impaired side of the cervical spinal cord in LOTUS-Tg rats. Moreover, electrophysiological analysis showed that contralesional cortex stimulation significantly increased ipsilateral forelimb movement in LOTUS-Tg rats, which was consistent with the histological findings. According to these data, LOTUS overexpression accelerates ipsilateral projection from the unlesioned cortex and promotes functional recovery after unilateral pyramidotomy. LOTUS could be a future therapeutic option for CNS injury.


Assuntos
Regeneração Nervosa/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Plasticidade Neuronal/fisiologia , Tratos Piramidais/lesões , Recuperação de Função Fisiológica/fisiologia , Animais , Axônios/metabolismo , Medula Cervical/metabolismo , Modelos Animais de Doenças , Receptor Nogo 1/metabolismo , Ratos , Ratos Transgênicos , Ratos Wistar
18.
Biochem Biophys Res Commun ; 523(2): 411-415, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-31870549

RESUMO

Pou3f2/Brn2 is a transcription factor that helps to determine the cellular identity of neocortical or hypothalamic neurons. Mammalian Pou3f2 contains three homopolymeric amino acids that are not present in amphibian Pou3f2. These amino acids contribute to monoamine function, which may play specific roles in mammalian development and behavior. Previous work has indicated that Pou3f2⊿ mice, which lack the homopolymeric amino acids, exhibited declined maternal activity and impaired object and spatial recognition. The current study, analyzed weight gain, brain development, home cage activity, social interaction, and response to novel objects in Pou3f2⊿ mice to determine which aspects of behavior were affected by monoamine dysregulation. Compared to their wild type counterparts, Pou3f2⊿ mice showed decreased social interaction and reduced home cage activity during their active phase. However, they showed normal weight gain, brain development, and responses to novelty. These results indicate that monoamine dysregulation in Pou3f2⊿ mice may specifically affect basal activity and social development, without altering non-social motivation.


Assuntos
Comportamento Animal/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Fatores do Domínio POU/fisiologia , Comportamento Social , Animais , Monoaminas Biogênicas/fisiologia , Encéfalo/crescimento & desenvolvimento , Comportamento Exploratório/fisiologia , Hipotálamo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neocórtex/fisiologia , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Neurônios/fisiologia , Fatores do Domínio POU/química , Fatores do Domínio POU/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Ganho de Peso
19.
Cell Biol Int ; 44(3): 894-904, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31868265

RESUMO

Disabled-2 (Dab2) and PAR-3 (partitioning defective 3) are reported to play critical roles in maintaining retinal microvascular endothelial cells biology by regulating VEGF-VEGFR-2 signaling. The role of Dab2 and PAR-3 in glomerular endothelial cell (GEnC) is unclear. In this study, we found that, no matter whether with vascular endothelial growth factor (VEGF) treatment or not, decreased expression of Dab2 could lead to cell apoptosis by preventing activation of VEGF-VEGFR-2 signaling in GEnC, accompanied by reduced membrane VEGFR-2 expression. And silencing of PAR-3 gene expression caused increased apoptosis of GEnC by inhibiting activation of VEGF-VEGFR-2 signaling and membrane VEGFR-2 expression. In our previous research, we found that the silencing of syndecan-1 gene expression inhibited VEGF-VEGFR-2 signaling by modulating internalization of VEGFR-2. And our further research demonstrated that downregulation of syndecan-1 lead to no significant change in the expression of Dab2 and PAR-3 both at messenger RNA and protein levels in GEnC, while phosphorylation of Dab2 was significantly increased in GEnC transfected with Dab2 small interfering RNA (siRNA) compared with control siRNA. Atypical protein kinase C (aPKC) could induce phosphorylation of Dab2, thus negatively regulating VEGF-VEGFR-2 signaling. And we found that decreased expression of syndecan-1 lead to activation of aPKC, and aPKC inhibitor treatment could block phosphorylation of Dab2 in GEnC. Besides, aPKC inhibitor treatment could activate VEGF-VGEFR-2 signaling in GEnC transfected with syndecan-1 siRNA in a dose-dependent manner. In conclusion, we speculated that phosphorylation of Dab2 is involved in preventing activation of VEGF-VEGFR-2 signaling in GEnC transfected with syndecan-1 siRNA. This provides a new target for the therapy of GEnC injury and kidney disease.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/fisiologia , Células Endoteliais/metabolismo , Glomérulos Renais/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Animais , Apoptose , Células Cultivadas , Células Endoteliais/citologia , Glomérulos Renais/citologia , Proteína Quinase C/metabolismo , Ratos , Sindecana-1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
20.
J Cell Biol ; 219(1)2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31820781

RESUMO

Appropriate axon guidance is necessary to form accurate neuronal connections. Axon guidance cues that stimulate cytoskeletal reorganization within the growth cone direct axon navigation. Filopodia at the growth cone periphery have long been considered sensors for axon guidance cues, yet how they respond to extracellular cues remains ill defined. Our previous work found that the filopodial actin polymerase VASP and consequently filopodial stability are negatively regulated via nondegradative TRIM9-dependent ubiquitination. Appropriate VASP ubiquitination and deubiquitination are required for axon turning in response to the guidance cue netrin-1. Here we show that the TRIM9-related protein TRIM67 outcompetes TRIM9 for interacting with VASP and antagonizes TRIM9-dependent VASP ubiquitination. The surprising antagonistic roles of two closely related E3 ubiquitin ligases are required for netrin-1-dependent filopodial responses, axon turning and branching, and fiber tract formation. We suggest a novel model in which coordinated regulation of VASP ubiquitination by a pair of interfering ligases is a critical element of VASP dynamics, filopodial stability, and axon guidance.


Assuntos
Orientação de Axônios/fisiologia , Moléculas de Adesão Celular/metabolismo , Proteínas do Citoesqueleto/fisiologia , Proteínas dos Microfilamentos/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Netrina-1/metabolismo , Fosfoproteínas/metabolismo , Pseudópodes/fisiologia , Proteínas com Motivo Tripartido/fisiologia , Ubiquitina-Proteína Ligases/fisiologia , Ubiquitina/metabolismo , Animais , Moléculas de Adesão Celular/genética , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas dos Microfilamentos/genética , Netrina-1/genética , Neurônios/citologia , Neurônios/metabolismo , Fosfoproteínas/genética , Ubiquitinação
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