RESUMO
In the developing spinal cord, motor neurons (MNs) and oligodendrocytes arise sequentially from a common pool of progenitors. However, the genetic network responsible for this neurogenesis to gliogenesis switch is largely unknown. A transcriptome analysis identified the Notch ligand Jagged2 (JAG2) as a Sonic hedgehog-regulated factor transiently expressed in MN progenitors (pMNs). In vivo loss- and gain-of-function experiments show that JAG2 schedules the differentiation of the pMN progenitors. At early developmental stages, Olig2 expressing pMN progenitors that enter the differentiation pathway exclusively generate MNs. At these times, the activation of the Notch pathway by JAG2 maintains selected pMN progenitors in an undifferentiated state by two mechanisms; first it inhibits MN generation by reducing Olig2 proteins levels, and second it directly inhibits the premature generation of oligodendrocyte progenitors (OLPs) by maintaining high levels of Hes5. Later, extinction of JAG2 from the pMN results in the loss of Hes5 expression, heralding the gliogenic phase of pMN progenitors. Strikingly, downregulation of JAG2 in pMN progenitors is sufficient to promote the precocious generation of OLPs. Together these data provide evidence that JAG2 is a key regulator of the timely and ordered generation of two of the defining cell types in the spinal cord, MNs and OLPs.
Assuntos
Proteínas de Membrana/metabolismo , Neurônios Motores/citologia , Oligodendroglia/citologia , Medula Espinal/citologia , Células-Tronco/citologia , Células-Tronco/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular , Embrião de Galinha , Proteínas Hedgehog/metabolismo , Humanos , Camundongos , Neurônios Motores/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Fator de Transcrição 2 de Oligodendrócitos , Oligodendroglia/metabolismo , Transdução de SinaisRESUMO
Increasing evidence suggests that CCN matricellular proteins play important roles in inflammation. One of the major cell types that handle inflammation in the brain is the astrocyte, which, upon activation, dramatically increases its production of cytokines and chemokines. Here, we report that NOV/CCN3, added to primary cultured rat brain astrocytes, markedly increased the expression of CCL2 and CXCL1 chemokines, as indicated by ELISA and RT-qPCR assays. This effect was selective, as the production of thirteen other cytokines and chemokines was not affected by NOV. NOV expression by astrocytes was demonstrated by immunocytochemistry and Western blot analysis, and astrocyte transfection with NOV small interfering RNA (siRNA) markedly decreased CXCL1 and CCL2 production, indicating that endogenous NOV played a major role in the control of astrocytic chemokine synthesis. NOV was shown to mediate several of its actions through integrins. Here, we observed that siRNAs against integrins beta1 and beta5 decreased basal and abrogated NOV-stimulated astrocyte expression of CCL2 and CXCL1, respectively. Using a panel of kinase inhibitors, we demonstrated that NOV action on CCL2 and CXCL1 production involved a Rho/ROCK/JNK/NF-kappaB and a Rho/qROCK/p38/NF-kappaB pathway, respectively. Thus, distinct integrins and signaling mechanisms are involved in NOV-induced production of CCL2 and CXCL1 in astrocytes. Finally, astrocytic expression of NOV was detected in rat brain tissue sections, and NOV intracerebral injection increased CCL2 and CXCL1 brain levels in vivo. Altogether, our data shed light on the signaling pathways operated by NOV and strongly suggest that NOV mediates astrocyte activation and, therefore, might play a role in neuroinflammation.
Assuntos
Astrócitos/efeitos dos fármacos , Quimiocina CCL2/metabolismo , Quimiocina CXCL1/metabolismo , Cadeias beta de Integrinas/metabolismo , Integrina beta1/metabolismo , Proteína Sobre-Expressa em Nefroblastoma/farmacologia , Regulação para Cima/efeitos dos fármacos , Animais , Astrócitos/metabolismo , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Movimento Celular , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CXCL1/genética , Inibidores Enzimáticos/farmacologia , Ensaio de Imunoadsorção Enzimática/métodos , Masculino , Proteína Sobre-Expressa em Nefroblastoma/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Transfecção/métodosRESUMO
A body of evidence points to the matricial CCN proteins as key regulators of organogenesis. NOV/CCN3, a founder CCN member, is expressed in the developing central nervous system but its functions during neural development have not been studied yet. Here we describe the pattern of NOV expression during rat cerebellar postnatal development and show that NOV expression increases during the second postnatal week, a critical period for the maturation of granule neuron precursors (GNP). NOV transcripts are specifically produced by Purkinje neurons and NOV protein localises extracellularly in the molecular layer and the inner part of the external granule layer, at a key position to control GNP proliferation and migration. In vitro, NOV reduces Sonic Hedgehog-induced GNP proliferation through beta3 integrins and stimulation of GSK3-beta activity whereas NOV stimulates GNP migration through distinct RGD-dependent integrins. These findings identify a new paracrine role of NOV in the development of cerebellar granule neurons.
Assuntos
Cerebelo/citologia , Proteína Sobre-Expressa em Nefroblastoma/metabolismo , Neurônios/fisiologia , Células-Tronco/fisiologia , Animais , Movimento Celular/fisiologia , Proliferação de Células , Células Cultivadas , Cerebelo/crescimento & desenvolvimento , Cerebelo/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Integrina beta3/metabolismo , Proteína Sobre-Expressa em Nefroblastoma/genética , Neurônios/citologia , Oligopeptídeos/metabolismo , Comunicação Parácrina/fisiologia , Células de Purkinje/citologia , Células de Purkinje/fisiologia , Ratos , Ratos Wistar , Células-Tronco/citologiaAssuntos
Adenocarcinoma/etiologia , Esôfago de Barrett/cirurgia , Neoplasias Esofágicas/etiologia , Junção Esofagogástrica , Esofagoscopia/efeitos adversos , Fotocoagulação a Laser/efeitos adversos , Neoplasias Gástricas/etiologia , Adenocarcinoma/patologia , Idoso , Esôfago de Barrett/complicações , Esôfago de Barrett/diagnóstico , Biópsia , Transformação Celular Neoplásica , Neoplasias Esofágicas/patologia , Esofagoscopia/métodos , Refluxo Gastroesofágico/etiologia , Humanos , Fotocoagulação a Laser/métodos , Masculino , Dor/etiologia , Neoplasias Gástricas/patologiaRESUMO
Histologic diagnosis of tumors of the mediastinum is mandatory for therapeutic management. The location and the variety of tumors are responsible for diagnostic difficulties. Endosonography guided fine-needle biopsy is an efficient and safe procedure for the diagnosis of peridigestive masses. We report the case of a patient with a neuroendocrine tumor of the mediastinum revealed by a mass syndrome. The diagnosis was performed by endosonography guided needle biopsy.
Assuntos
Biópsia por Agulha/métodos , Endossonografia , Neoplasias do Mediastino/patologia , Tumores Neuroendócrinos/patologia , Esôfago , Evolução Fatal , Humanos , Masculino , Pessoa de Meia-IdadeAssuntos
Antibioticoprofilaxia/métodos , Bacteriemia/prevenção & controle , Doenças Biliares/prevenção & controle , Colangiopancreatografia Retrógrada Endoscópica/efeitos adversos , Endocardite Bacteriana/prevenção & controle , Bacteriemia/epidemiologia , Bacteriemia/etiologia , Doenças Biliares/epidemiologia , Doenças Biliares/etiologia , Doenças Biliares/microbiologia , Endocardite Bacteriana/epidemiologia , Endocardite Bacteriana/etiologia , Humanos , Incidência , Cuidados Pré-OperatóriosRESUMO
OBJECTIVES: The aim of this study was to analyze the evolution of treatment regimens and survival rates of stomach adenocarcinoma recorded in the Finistère cancer registry from 1984 to 1989. METHODS: In a population of 838,627 inhabitants, 1,280 patients with a gastric cancer were registered; 1,164 patients (693 males and 471 females) had an adenocarcinoma. Survival rates were estimated by the actuarial method, and compared using the logrank test and the Cox model. RESULTS: Surgical resection was the main treatment for 661 patients (57%). The frequency of curative resection increased from 25% between 1984 and 1986 to 35% after 1986. Among the other patients, 39 (3%) were treated by chemotherapy and/or radiotherapy, and 53 patients (4%) by endoscopy alone; 253 patients had only symptomatic treatment. The survival rates of all patients were 43% at 1 year and 20% at 5 years. The median survival was 9.2 +/- 0.6 months. In patients with cancer managed surgically, the factors associated with a better prognosis were young age, long duration of symptoms before diagnosis, ulcerated macroscopic aspect, limited tumour extension and curative surgical resection. In other patients, 2 factors were associated a with better prognosis: the absence of metastases and an endoscopic palliative treatment. CONCLUSIONS: Surgical resection is the main treatment of gastric adenocarcinoma. Although the frequency of surgery increased, the prognosis of gastric adenocarcinoma did not improve within this 6-year period.