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1.
Nat Neurosci ; 22(7): 1089-1098, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31235908

RESUMO

Pericytes are positioned between brain capillary endothelial cells, astrocytes and neurons. They degenerate in multiple neurological disorders. However, their role in the pathogenesis of these disorders remains debatable. Here we generate an inducible pericyte-specific Cre line and cross pericyte-specific Cre mice with iDTR mice carrying Cre-dependent human diphtheria toxin receptor. After pericyte ablation with diphtheria toxin, mice showed acute blood-brain barrier breakdown, severe loss of blood flow, and a rapid neuron loss that was associated with loss of pericyte-derived pleiotrophin (PTN), a neurotrophic growth factor. Intracerebroventricular PTN infusions prevented neuron loss in pericyte-ablated mice despite persistent circulatory changes. Silencing of pericyte-derived Ptn rendered neurons vulnerable to ischemic and excitotoxic injury. Our data demonstrate a rapid neurodegeneration cascade that links pericyte loss to acute circulatory collapse and loss of PTN neurotrophic support. These findings may have implications for the pathogenesis and treatment of neurological disorders that are associated with pericyte loss and/or neurovascular dysfunction.


Assuntos
Proteínas de Transporte/fisiologia , Citocinas/fisiologia , Degeneração Neural/fisiopatologia , Proteínas do Tecido Nervoso/fisiologia , Neurônios/patologia , Pericitos/fisiologia , Choque/fisiopatologia , Animais , Isquemia Encefálica/fisiopatologia , Capilares/fisiopatologia , Proteínas de Transporte/uso terapêutico , Células Cultivadas , Circulação Cerebrovascular/fisiologia , Citocinas/deficiência , Citocinas/uso terapêutico , Células Endoteliais/citologia , Feminino , Genes Reporter , Infusões Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Degeneração Neural/tratamento farmacológico , Neuroglia/metabolismo , Neurônios/metabolismo , Neurotoxinas/toxicidade , Regiões Promotoras Genéticas , Proteínas Recombinantes de Fusão/metabolismo , Choque/metabolismo , Choque/patologia
2.
Nat Neurosci ; 22(7): 1110-1121, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31160741

RESUMO

Learning to predict rewards based on environmental cues is essential for survival. The orbitofrontal cortex (OFC) contributes to such learning by conveying reward-related information to brain areas such as the ventral tegmental area (VTA). Despite this, how cue-reward memory representations form in individual OFC neurons and are modified based on new information is unknown. To address this, using in vivo two-photon calcium imaging in mice, we tracked the response evolution of thousands of OFC output neurons, including those projecting to VTA, through multiple days and stages of cue-reward learning. Collectively, we show that OFC contains several functional clusters of neurons distinctly encoding cue-reward memory representations, with only select responses routed downstream to VTA. Unexpectedly, these representations were stably maintained by the same neurons even after extinction of the cue-reward pairing, and supported behavioral learning and memory. Thus, OFC neuronal activity represents a long-term cue-reward associative memory to support behavioral adaptation.


Assuntos
Adaptação Psicológica/fisiologia , Aprendizagem por Associação/fisiologia , Sinalização do Cálcio , Condicionamento Clássico/fisiologia , Memória de Longo Prazo/fisiologia , Neurônios/fisiologia , Córtex Pré-Frontal/fisiologia , Recompensa , Estimulação Acústica , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/fisiologia , Sinais (Psicologia) , Comportamento de Ingestão de Líquido/fisiologia , Extinção Psicológica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/fisiologia , Neurônios/enzimologia , Optogenética , Técnicas de Patch-Clamp , Córtex Pré-Frontal/citologia , Análise de Célula Única , Área Tegmentar Ventral/fisiologia
3.
Nat Neurosci ; 22(7): 1066-1074, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209380

RESUMO

Cannabis is the most frequently used illicit psychoactive substance worldwide; around one in ten users become dependent. The risk for cannabis use disorder (CUD) has a strong genetic component, with twin heritability estimates ranging from 51 to 70%. Here we performed a genome-wide association study of CUD in 2,387 cases and 48,985 controls, followed by replication in 5,501 cases and 301,041 controls. We report a genome-wide significant risk locus for CUD (P = 9.31 × 10-12) that replicates in an independent population (Preplication = 3.27 × 10-3, Pmeta-analysis = 9.09 × 10-12). The index variant (rs56372821) is a strong expression quantitative trait locus for cholinergic receptor nicotinic α2 subunit (CHRNA2); analyses of the genetically regulated gene expression identified a significant association of CHRNA2 expression with CUD in brain tissue. At the polygenic level, analyses revealed a significant decrease in the risk of CUD with increased load of variants associated with cognitive performance. The results provide biological insights and inform on the genetic architecture of CUD.


Assuntos
Abuso de Maconha/genética , Proteínas do Tecido Nervoso/fisiologia , Receptores Nicotínicos/fisiologia , Idade de Início , Alelos , Transtorno do Deficit de Atenção com Hiperatividade/genética , Encéfalo/metabolismo , Estudos de Casos e Controles , Cromossomos Humanos Par 8/genética , Cognição/fisiologia , Estudos de Coortes , Fatores de Confusão (Epidemiologia) , Dinamarca , Escolaridade , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Islândia , Masculino , Herança Multifatorial , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Receptores Nicotínicos/biossíntese , Receptores Nicotínicos/genética , Esquizofrenia/genética , Fumar/genética , Transcriptoma
4.
Sheng Li Xue Bao ; 71(2): 287-293, 2019 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-31008488

RESUMO

This study was aimed to examine the expression and function of Slit/Robo family members in mouse ovary. Real-time PCR was used to assess the mRNA expression levels of Slit/Robo family members, and immunohistochemistry was used to examine the location of Slit2 and Robo1 in the ovary. The mRNA and protein expression levels of Slit2 and Robo1 in early-, middle- and late-phase corpus luteum (CL) were examined by real-time PCR and immunohistochemistry, respectively. Blocking agent ROBO1/Fc chimera was used in the luteal cells in vitro to examine the function of Slit/Robo signaling pathway in mouse CL. The results showed that, among the Slit/Robo family members, the expression levels of ligand Slit2 and receptor Robo1 were the highest in mouse ovarian tissue. Moreover, both of them were specifically expressed in mouse luteal cells. Compared with proestrus ovaries, the expression levels of Slit2 and Robo1 mRNA in the ovaries during diestrus were significantly up-regulated (P < 0.01, P < 0.001). The mRNA expression levels of Slit2 and Robo1 in late-phase CL were significantly increased when compared with pregnant CL. Furthermore, blocking Slit/Robo signaling pathway with ROBO1/Fc chimera in the luteal cells in vitro significantly decreased the apoptotic rate of late luteal cells. These results suggest that Slit/Robo family members are mainly expressed in the late-phase CL of ovary and participate in luteal cells apoptosis.


Assuntos
Apoptose , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Células Lúteas/citologia , Proteínas do Tecido Nervoso/fisiologia , Receptores Imunológicos/fisiologia , Animais , Feminino , Camundongos , Gravidez
5.
Nat Commun ; 10(1): 1518, 2019 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-30944331

RESUMO

When migrating in vivo, cells are exposed to numerous conflicting signals: chemokines, repellents, extracellular matrix, growth factors. The roles of several of these molecules have been studied individually in vitro or in vivo, but we have yet to understand how cells integrate them. To start addressing this question, we used the cephalic neural crest as a model system and looked at the roles of its best examples of positive and negative signals: stromal-cell derived factor 1 (Sdf1/Cxcl12) and class3-Semaphorins. Here we show that Sdf1 and Sema3A antagonistically control cell-matrix adhesion via opposite effects on Rac1 activity at the single cell level. Directional migration at the population level emerges as a result of global Semaphorin-dependent confinement and broad activation of adhesion by Sdf1 in the context of a biased Fibronectin distribution. These results indicate that uneven in vivo topology renders the need for precise distribution of secreted signals mostly dispensable.


Assuntos
Movimento Celular/fisiologia , Junções Célula-Matriz/fisiologia , Crista Neural/citologia , Animais , Adesão Celular/efeitos dos fármacos , Adesão Celular/fisiologia , Comunicação Celular/fisiologia , Linhagem Celular , Forma Celular/efeitos dos fármacos , Extensões da Superfície Celular/efeitos dos fármacos , Junções Célula-Matriz/efeitos dos fármacos , Junções Célula-Matriz/metabolismo , Quimiocina CXCL12/metabolismo , Feminino , Fibronectinas/metabolismo , Masculino , Manganês/metabolismo , Camundongos , Proteínas do Tecido Nervoso/fisiologia , Crista Neural/efeitos dos fármacos , Crista Neural/metabolismo , Receptores CXCR4/metabolismo , Semaforinas/metabolismo , Xenopus laevis/embriologia , Proteínas rac1 de Ligação ao GTP/metabolismo
7.
Cell Mol Biol Lett ; 24: 19, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30891073

RESUMO

Background: Cyclin-dependent kinase-like 1 (CDKL1) is a member of the cell division control protein 2-related serine-threonine protein kinase family. It is known to occur in various malignant tumors, but its role in neuroblastoma (NB) remains unclear. Methods: We constructed a CDKL1-silenced NB cell strain (SH-SY5Y) and used real-time PCR and western blotting to confirm the silencing. Functional analyses were performed using the MTT, colony-formation, FACS, wound-healing and transwell invasion assays. Results: The expression of CDKL1 was significantly upregulated in NB tissue as compared to the adjacent normal tissue. CDKL1 knockdown significantly suppressed cell viability and colony formation ability. It also induced cell cycle G0/G1 phase arrest and apoptosis, and suppressed the migration and invasion ability of SH-SY5Y cells. CDKL1 knockdown decreased the CDK4, cyclin D1 and vimentin expression levels, and increased the caspase-3, PARP and E-cadherin expression levels in SH-SY5Y cells. Conclusions: Our findings suggest that CDKL1 plays an important role in NB cell proliferation, migration and invasion. It might serve as a potential target for NB therapy.


Assuntos
Movimento Celular , Proliferação de Células , Quinases Ciclina-Dependentes/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Neuroblastoma/genética , Apoptose , Linhagem Celular Tumoral , Quinases Ciclina-Dependentes/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica , Proteínas do Tecido Nervoso/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Neuroblastoma/fisiopatologia
8.
Neurosci Bull ; 35(3): 497-506, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30790215

RESUMO

Neuroligins (NLs) are postsynaptic cell-adhesion proteins that play important roles in synapse formation and the excitatory-inhibitory balance. They have been associated with autism in both human genetic and animal model studies, and affect synaptic connections and synaptic plasticity in several brain regions. Yet current research mainly focuses on pyramidal neurons, while the function of NLs in interneurons remains to be understood. To explore the functional difference among NLs in the subtype-specific synapse formation of both pyramidal neurons and interneurons, we performed viral-mediated shRNA knockdown of NLs in cultured rat cortical neurons and examined the synapses in the two major types of neurons. Our results showed that in both types of neurons, NL1 and NL3 were involved in excitatory synapse formation, and NL2 in GABAergic synapse formation. Interestingly, NL1 affected GABAergic synapse formation more specifically than NL3, and NL2 affected excitatory synapse density preferentially in pyramidal neurons. In summary, our results demonstrated that different NLs play distinct roles in regulating the development and balance of excitatory and inhibitory synapses in pyramidal neurons and interneurons.


Assuntos
Moléculas de Adesão Celular Neuronais/fisiologia , Interneurônios/fisiologia , Proteínas de Membrana/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Células Piramidais/fisiologia , Sinapses/fisiologia , Animais , Células Cultivadas , Córtex Cerebral/embriologia , Córtex Cerebral/fisiologia , Neurônios GABAérgicos/fisiologia , Isoformas de Proteínas/fisiologia , Ratos Sprague-Dawley
9.
Psychiatr Genet ; 29(2): 44-50, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30664045

RESUMO

BACKGROUND: Several lines of evidence support the hypothesis that impaired functioning of the glutamatergic N-methyl-D-aspartate receptor (NMDAR) might be involved in the etiology of schizophrenia. NMDAR is activated by phosphorylation by Fyn, and there is also some evidence to suggest that abnormalities in Fyn functionality could also be involved in susceptibility to schizophrenia. In a recent weighted burden analysis of exome-sequenced schizophrenia cases and controls, we noted modest statistical evidence for an enrichment of rare, functional variants in FYN, GRIN1, and GRIN2B in schizophrenia cases. AIM: To test the plausibility of the hypothesis that schizophrenia susceptibility might be associated with genetic variants predicted to cause impaired functioning of NMDAR, either directly or indirectly through impairment of the kinases that phosphorylate it. METHODS: In an exome-sequenced sample of 4225 schizophrenia cases and 5834 controls, rare variants occurring in genes for the NMDAR subunits and for the kinases acting on it were annotated. The counts of disruptive and damaging variants were compared between cases and controls, and the distribution of amino acids affected by damaging variants was visualised in ProteinPaint and the RCSB Protein Data Bank. Special attention was paid to tyrosine residues subject to phosphorylation. RESULTS: There was no suggestion that abnormalities of the serine-threonine kinases or of Src were associated with schizophrenia. Overall, three cases and no controls had a disruptive variant in GRIN2A and two cases and no controls had a disruptive variant in FYN. Moreover, 14 cases and three controls had damaging variants in FYN, and all the variants in controls affected amino acid residues in the N-terminal region outside of any known functional domains. By contrast, 10 variants in cases affected amino acids in functional domains, and in the 3D structure of Fyn, two of the amino acid substitutions, A376T and Q517E, were adjacent to each other. A total of eight cases and one control had damaging variants in GRIN1, but there was no obvious pattern with respect to particular functional domains being affected in this or other genes. A single case had a variant in GRIN2A affecting a well-supported phosphorylation site, Y943C, and three cases had a variant in FYN which produces an amino acid change, T216S, which lies two residues away from two adjacent well-supported phosphorylation sites. Aside from this, there was no suggestion that tyrosine phosphorylation sites in Fyn or NMDAR were affected. CONCLUSION: The numbers of variants involved are too small for firm conclusions to be drawn. The results are consistent with the hypothesis that ∼0.5% of patients with schizophrenia have disruptive or damaging genetic variants, which could plausibly impair functioning of NMDAR directly or indirectly through impairing Fyn function.


Assuntos
Receptores de N-Metil-D-Aspartato/genética , Esquizofrenia/genética , Adulto , Estudos de Casos e Controles , Simulação por Computador , Feminino , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Fosforilação , Proteínas Proto-Oncogênicas c-fyn/genética , Proteínas Proto-Oncogênicas c-fyn/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Sequenciamento Completo do Exoma/métodos
10.
Neuroscience ; 402: 116-129, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30685539

RESUMO

The facial nerve is necessary for our ability to eat, speak, and make facial expressions. Both the axons and cell bodies of the facial nerve undergo a complex embryonic developmental pattern involving migration of the cell bodies caudally and tangentially through rhombomeres, and simultaneously the axons projecting to exit the hindbrain to form the facial nerve. Our goal in this study was to test the functions of the chemorepulsive receptors Robo1 and Robo2 in facial neuron migration and axon projection by analyzing genetically marked motor neurons in double-mutant mouse embryos through the migration time course, E10.0-E13.5. In Robo1/2 double mutants, axon projection and cell body migration errors were more severe than in single mutants. Most axons did not make it to their motor exit point, and instead projected into and longitudinally within the floor plate. Surprisingly, some facial neurons had multiple axons exiting and projecting into the floor plate. At the same time, a subset of mutant facial cell bodies failed to migrate caudally, and instead either streamed dorsally toward the exit point or shifted into the floor plate. We conclude that Robo1 and Robo2 have redundant functions to guide multiple aspects of the complex cell migration of the facial nucleus, as well as regulating axon trajectories and suppressing formation of ectopic axons.


Assuntos
Orientação de Axônios , Axônios/fisiologia , Movimento Celular , Nervo Facial/embriologia , Proteínas do Tecido Nervoso/fisiologia , Receptores Imunológicos/fisiologia , Rombencéfalo/embriologia , Animais , Camundongos Transgênicos , Neurônios Motores/fisiologia
12.
Behav Brain Res ; 356: 98-106, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29885845

RESUMO

Vascular dementia (VD) is a heterogeneous group of brain disorders in which cognitive impairment is attributed to cerebrovascular pathologies. Autophagy, a self-cannibalization mechanism, has been demonstrated to be involved in VD progression. Molecular hydrogen is known for its powerful anti-oxidative, anti-apoptotic, and anti-inflammatory activities, and it is also involved in autophagy. However, the effects of hydrogen on VD remain unclear. The current study found that hydrogen-rich water (HRW) significantly alleviated spatial learning and memory impairments. Similar to donepezil treatment, HRW also inhibited neuron loss and shrinkage in the hippocampal CA1 region. In addition, we found that HRW significantly increased the Bcl-2/Bax expression ratio and decreased cleaved caspase-3 expression levels in the hippocampus of VD rats. Moreover, electron microscopy revealed that HRW decreased the number of autophagosomes. We also observed that HRW reduced the increased ratio of LC3-II/I and Beclin 1 expression and saliently upregulated p62 expression. Furthermore, FoxO1 (a major mediator of autophagy regulation) and Atg7 levels were apparently decreased in the hippocampus of HRW-treated bilateral common carotid artery occlusion (2VO) rats. Taken together, these data show that molecular hydrogen exerts beneficial effects on cognitive impairment induced by chronic cerebral hypoperfusion. FoxO1-mediated autophagy plays an important role in the neuroprotective effects of hydrogen in a rat model of VD. Furthermore, the present findings highlight that HRW should be further investigated as a new therapeutic strategy for VD treatment in the future.


Assuntos
Demência Vascular/metabolismo , Hidrogênio/farmacologia , Proteínas do Tecido Nervoso/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autofagia/fisiologia , Proteína Beclina-1/metabolismo , Isquemia Encefálica/patologia , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Caspase 3/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Demência Vascular/fisiopatologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hidrogênio/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Proteínas do Tecido Nervoso/fisiologia , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Aprendizagem Espacial/efeitos dos fármacos
13.
Nat Commun ; 9(1): 5400, 2018 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-30573727

RESUMO

Abnormalities in synaptic inhibition play a critical role in psychiatric disorders, and accordingly, it is essential to understand the molecular mechanisms linking components of the inhibitory postsynapse to psychiatrically relevant neural circuits and behaviors. Here we study the role of IgSF9b, an adhesion protein that has been associated with affective disorders, in the amygdala anxiety circuitry. We show that deletion of IgSF9b normalizes anxiety-related behaviors and neural processing in mice lacking the synapse organizer Neuroligin-2 (Nlgn2), which was proposed to complex with IgSF9b. This normalization occurs through differential effects of Nlgn2 and IgSF9b at inhibitory synapses in the basal and centromedial amygdala (CeM), respectively. Moreover, deletion of IgSF9b in the CeM of adult Nlgn2 knockout mice has a prominent anxiolytic effect. Our data place IgSF9b as a key regulator of inhibition in the amygdala and indicate that IgSF9b-expressing synapses in the CeM may represent a target for anxiolytic therapies.


Assuntos
Tonsila do Cerebelo/metabolismo , Transtornos de Ansiedade/genética , Proteínas de Membrana/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Sinapses/metabolismo , Tonsila do Cerebelo/fisiologia , Animais , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/fisiologia , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Interferência de RNA , Transmissão Sináptica/genética
14.
Elife ; 72018 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-30082022

RESUMO

Growth cones navigate axonal projection in response to guidance cues. However, it is unclear how they can decide the migratory direction by transducing the local spatial cues into protrusive forces. Here we show that knockout mice of Shootin1 display abnormal projection of the forebrain commissural axons, a phenotype similar to that of the axon guidance molecule netrin-1. Shallow gradients of netrin-1 elicited highly polarized Pak1-mediated phosphorylation of shootin1 within growth cones. We demonstrate that netrin-1-elicited shootin1 phosphorylation increases shootin1 interaction with the cell adhesion molecule L1-CAM; this, in turn, promotes F-actin-adhesion coupling and concomitant generation of forces for growth cone migration. Moreover, the spatially regulated shootin1 phosphorylation within growth cones is required for axon turning induced by netrin-1 gradients. Our study defines a mechano-effector for netrin-1 signaling and demonstrates that shootin1 phosphorylation is a critical readout for netrin-1 gradients that results in a directional mechanoresponse for axon guidance.


Assuntos
Orientação de Axônios/fisiologia , Quimiotaxia , Embrião de Mamíferos/fisiologia , Cones de Crescimento/fisiologia , Mecanotransdução Celular , Proteínas do Tecido Nervoso/fisiologia , Netrina-1/metabolismo , Actinas/metabolismo , Animais , Adesão Celular , Células Cultivadas , Embrião de Mamíferos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Netrina-1/genética , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Fosforilação , Ratos , Ratos Wistar , Transdução de Sinais , Quinases Ativadas por p21/genética , Quinases Ativadas por p21/metabolismo
15.
Yakugaku Zasshi ; 138(8): 1017-1024, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-30068841

RESUMO

Various neuropeptides play an essential role in the nutrient sensing mechanism and related homeostasis. Nesfatin-1 is a newly identified neuropeptide having anorectic activity, and nesfatin-1-containing neurons are widely distributed in the brain, including the hypothalamus and brain stem. Our previous study showed that dehydration-induced anorectic effects are mediated via the central nesfatin-1 pathway in rats. Our recent studies have also shown that peripheral anorectic peptides (cholecystokinin-8, glucagon-like peptide-1, and leptin) and an antineoplastic agent (cisplatin) caused inhibition of feeding via the central nesfatin-1 pathway in rats. Nesfatin-1-containing neurons in the central nervous system, in particular the hypothalamus and the brain stem, may mediate peripheral nutrient signals and regulate feeding behavior.


Assuntos
Anorexia/etiologia , Anorexia/genética , Colecistocinina/fisiologia , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/genética , Alimentos , Peptídeo 1 Semelhante ao Glucagon/fisiologia , Leptina/fisiologia , Fenômenos Fisiológicos da Nutrição/genética , Fenômenos Fisiológicos da Nutrição/fisiologia , Transdução de Sinais/fisiologia , Animais , Antineoplásicos/efeitos adversos , Tronco Encefálico/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/fisiologia , Colecistocinina/metabolismo , Cisplatino/efeitos adversos , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/fisiologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hipotálamo/metabolismo , Leptina/metabolismo , Masculino , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Ratos Wistar
16.
Proc Natl Acad Sci U S A ; 115(33): 8370-8375, 2018 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-30061407

RESUMO

The tumor suppressor p53 regulates multiple cellular functions, including energy metabolism. Metabolic deregulation is implicated in the pathogenesis of some cancers and in metabolic disorders and may result from the inactivation of p53 functions. Using RNA sequencing and ChIP sequencing of cancer cells and preadipocytes, we demonstrate that p53 modulates several metabolic processes via the transactivation of energy metabolism genes including dihydropyrimidinase-like 4 (DPYSL4). DPYSL4 is a member of the collapsin response mediator protein family, which is involved in cancer invasion and progression. Intriguingly, DPYSL4 overexpression in cancer cells and preadipocytes up-regulated ATP production and oxygen consumption, while DPYSL4 knockdown using siRNA or CRISPR/Cas9 down-regulated energy production. Furthermore, DPYSL4 was associated with mitochondrial supercomplexes, and deletion of its dihydropyrimidinase-like domain abolished its association and its ability to stimulate ATP production and suppress the cancer cell invasion. Mouse-xenograft and lung-metastasis models indicated that DPYSL4 expression compromised tumor growth and metastasis in vivo. Consistently, database analyses demonstrated that low DPYSL4 expression was significantly associated with poor survival of breast and ovarian cancers in accordance with its reduced expression in certain types of cancer tissues. Moreover, immunohistochemical analysis using the adipose tissue of obese patients revealed that DPYSL4 expression was positively correlated with INFg and body mass index in accordance with p53 activation. Together, these results suggest that DPYSL4 plays a key role in the tumor-suppressor function of p53 by regulating oxidative phosphorylation and the cellular energy supply via its association with mitochondrial supercomplexes, possibly linking to the pathophysiology of both cancer and obesity.


Assuntos
Adipócitos/metabolismo , Metabolismo Energético , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Proteína Supressora de Tumor p53/fisiologia , Trifosfato de Adenosina/biossíntese , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos SCID , Obesidade/metabolismo , Consumo de Oxigênio , Proteínas Supressoras de Tumor/fisiologia
17.
J Mol Histol ; 49(5): 509-518, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30120609

RESUMO

Nuclear localization leucine-rich-repeat protein 1 (NLRP1) is a member of Nod-like receptors (NLRs) family. Recent studies have reported that NLRP1 is involved in various diseases, especially in cardiovascular diseases. However, the effect of NLRP1 on cardiac fibrosis remains unclear. In this study, NLRP1 overexpression and NLRP1 silencing constructs were transfected into neonatal rat cardiac fibroblasts induced by TGF-ß1 for 48 h to investigate the effect of NLRP1 in cardiac fibrosis and its molecular mechanisms. Cardiac fibroblasts were transfected with NLRP1 and then cultured in the presence and absence of TGF-ß1and Smad3 inhibitor (SIS3). Our data indicated that NLRP1 not only promoted fibroblast activation and myofibroblast differentiation, but also upregulated the mRNA and protein levels of α-SMA in the TGF-ß1-treated neonatal rat cardiac fibroblasts. Overexpressing NLRP1 in TGF-ß1-induced cardiac fibroblasts upregulated the mRNA and protein levels of Collagen I, Collagen III, and connective tissue growth factor. Moreover, NLRP1 upregulated the protein levels of Smad2, Smad3, and Smad4 in nuclei of fibroblasts, and attenuated levels of phosphorylated Smad2 and Smad3 in the cytoplasm of fibroblasts induced by TGF-ß1. In addition, the increase in fibrotic genes and Smad proteins was significantly reduced in the presence of SIS3. Our findings illustrated that NLRP1 promoted myofibroblast differentiation and excessive ECM production in TGF-ß1-induced neonatal cardiac fibroblasts through directly targeting TGF-ß1/Smad signaling pathways.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Miocárdio/citologia , Miofibroblastos/citologia , Proteínas do Tecido Nervoso/fisiologia , Fator de Crescimento Transformador beta1/farmacologia , Animais , Animais Recém-Nascidos , Colágeno Tipo I/metabolismo , Colágeno Tipo III/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Miofibroblastos/metabolismo , Ratos , Transdução de Sinais , Proteínas Smad/metabolismo
18.
Clin Dysmorphol ; 27(4): 113-115, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29939863

RESUMO

Autism spectrum disorder (ASD) encompasses a spectrum of pervasive neuropsychiatric disorders characterized by deficits in social interaction, communication, unusual and repetitive behaviours. The aetiology of ASD is believed to involve complex interactions between genetic and environmental factors; it can be further classified as syndromic or nonsyndromic, according to whether it is the primary diagnosis or secondary to an existing condition where both common and rare genetic variants contribute to the development of ASD or are clearly causal. The prevalence of ASD in children is increasing with higher rates of diagnosis and an estimated one in 100 affected in the UK. Given that heritability is a major contributing factor, we aim to discuss research findings to-date in the context of a high-risk autism candidate gene, SHANK3 (SH3 and multiple ankyrin repeat domain 3), with its loss resulting in synaptic function disruption. We present a 10-year-old patient with a pathogenic de novo heterozygous c.1231delC, p.Arg411Val frameshift variant in SHANK3. He presented with severe autism, attention deficit hyperactivity disorder and pathological demand avoidance, on a background of developmental impairment and language regression. The number of genes associated with autism is ever increasing. It is a heterogeneous group of disorders with no single gene conferring pathogenesis in the majority of cases. Genetic abnormalities can be detected in ~15% of ASD and these range from copy number variants in 16p11.2 and 15q13.2q13.3 to several well-known genetic disorders including tuberous sclerosis and fragile X syndrome. Further, high confidence autism genes include but are not limited to NRXN, NLGN3, NLGN4, SHANK2 and SHANK3.


Assuntos
Transtorno Autístico/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/fisiopatologia , Transtorno Autístico/fisiopatologia , Criança , Variações do Número de Cópias de DNA/genética , Variação Genética , Humanos , Masculino
19.
Dev Dyn ; 247(8): 965-975, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29770538

RESUMO

BACKGROUND: In the developing mouse embryo, the bHLH transcription factor Neurog2 is transiently expressed by retinal progenitor cells and required for the initial wave of neurogenesis. Remarkably, another bHLH factor, Ascl1, normally not present in the embryonic Neurog2 retinal lineage, can rescue the temporal phenotypes of Neurog2 mutants. RESULTS: Here we show that Neurog2 simultaneously promotes terminal cell cycle exit and retinal ganglion cell differentiation, using mitotic window labeling and integrating these results with retinal marker quantifications. We also analyzed the transcriptomes of E12.5 GFP-expressing cells from Neurog2GFP/+ , Neurog2GFP/GFP , and Neurog2Ascl1KI/GFP eyes, and validated the most significantly affected genes using qPCR assays. CONCLUSIONS: Our data support the hypothesis that Neurog2 acts at the top of a retinal bHLH transcription factor hierarchy. The combined expression levels of these downstream factors are sufficiently induced by ectopic Ascl1 to restore RGC genesis, highlighting the robustness of this gene network during retinal ganglion cell neurogenesis. Developmental Dynamics 247:965-975, 2018. © 2018 Wiley Periodicals, Inc.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Ciclo Celular , Proteínas do Tecido Nervoso/fisiologia , Neurogênese , Células Ganglionares da Retina/citologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Embrião de Mamíferos , Camundongos , Transcriptoma/efeitos dos fármacos
20.
Mol Cells ; 41(5): 454-464, 2018 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-29754475

RESUMO

Crosstalk between G-protein signaling and glutamatergic transmission within the brain reward circuits is critical for long-term emotional effects (depression and anxiety), cravings, and negative withdrawal symptoms associated with opioid addiction. A previous study showed that Regulator of G-protein signaling 4 (RGS4) may be implicated in opiate action in the nucleus accumbens (NAc). However, the mechanism of the NAc-specific RGS4 actions that induce the behavioral responses to opiates remains largely unknown. The present study used a short hairpin RNA (shRNA)-mediated knock-down of RGS4 in the NAc of the mouse brain to investigate the relationship between the activation of ionotropic glutamate receptors and RGS4 in the NAc during morphine reward. Additionally, the shRNA-mediated RGS4 knock-down was implemented in NAc/striatal primary-cultured neurons to investigate the role that striatal neurons have in the morphine-induced activation of ionotropic glutamate receptors. The results of this study show that the NAc-specific knockdown of RGS4 significantly increased the behaviors associated with morphine and did so by phosphorylation of the GluR1 (Ser831) and NR2A (Tyr1325) glutamate receptors in the NAc. Furthermore, the knock-down of RGS4 enhanced the phosphorylation of the GluR1 and NR2A glutamate receptors in the primary NAc/striatal neurons during spontaneous morphine withdrawal. These findings show a novel molecular mechanism of RGS4 in glutamatergic transmission that underlies the negative symptoms associated with morphine administration.


Assuntos
Ácido Glutâmico/fisiologia , Morfina/farmacologia , Proteínas do Tecido Nervoso/fisiologia , Núcleo Accumbens/fisiologia , Proteínas RGS/fisiologia , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Recompensa , Animais , Células Cultivadas , Corpo Estriado/citologia , Comportamento Exploratório/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/genética , Núcleo Accumbens/citologia , Núcleo Accumbens/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas RGS/antagonistas & inibidores , Proteínas RGS/genética , Interferência de RNA , RNA Interferente Pequeno/genética
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