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1.
J Neurosci ; 33(20): 8794-809, 2013 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-23678122

RESUMEN

The striatopallidal (STP) and striatonigral (STN) neurons constitute the main neuronal populations of the striatum. Despite the increasing knowledge concerning their involvement in multiple tasks associated with the striatum, it is still challenging to understand the precise differential functions of these two neuronal populations and to identify and study new genes involved in these functions. Here, we describe a reliable approach, applied on adult mouse brain, to generate specific STP and STN neuron gene profiles. STP and STN neurons were identified in the same animal using the transgenic Adora2A-Cre × Z/EG mouse model combined with retrograde labeling, respectively. Gene profiling was generated from FACS-purified neurons leading to the identification of new STP and STN neuron-specific genes. Knock-down models based on Cre-dependent lentiviral vector were developed to investigate their function either in striatal or in STP neurons. Thereby, we demonstrate that ecto-5'-nucleotidase (NT5e) is specifically expressed in STP neurons and is at the origin of most of the extracellular adenosine produced in the striatum. Behavioral analysis of striatal and STP neuron knock-down mouse models as well as NT5e knock-out mice demonstrates the implication of this STP neuron enzyme in motor learning.


Asunto(s)
5'-Nucleotidasa/metabolismo , Cuerpo Estriado/fisiología , Aprendizaje/fisiología , Proteínas del Tejido Nervioso/metabolismo , Neuronas/fisiología , 5'-Nucleotidasa/genética , Animales , Cuerpo Estriado/citología , Citometría de Flujo , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Técnicas de Transferencia de Gen , Globo Pálido/citología , Proteínas Fluorescentes Verdes/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Destreza Motora/fisiología , Proteínas del Tejido Nervioso/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/metabolismo , Receptor de Adenosina A2A/genética , Receptores de Dopamina D2/genética
2.
Ann Rheum Dis ; 73(6): 1259-63, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24385203

RESUMEN

OBJECTIVES: To investigate the role of the interleukin (IL)-33-ST2 axis in the pathophysiology of primary Sjögren's syndrome (pSS). METHODS: Serum levels of IL-33 and sST2 were determined by ELISA. The expression of IL-33 and ST2 was investigated in salivary glands (SG) by immunohistochemistry. PBMC were isolated and stimulated with IL-33, IL-12 and IL-23 and the cytokine profile response was examined by flow cytometry. Intracellular cytokine detection of IFNγ and IL-17 was performed by flow cytometry. RESULTS: Serum IL-33 and sST2 levels were increased in pSS patients compared with controls and patients with systemic lupus erythematosus. Expression of IL-33 was upregulated in SG with Chisholm scores of 2 and 3 of pSS patients but comparable with controls for SG with Chisholm score of 4. ST2 expression in SG was downregulated in pSS patients. IL-33 at different concentrations did not increase the secretion of pro-inflammatory cytokines but acted synergistically with IL-12 and IL-23 to promote IFNγ production. NK and NKT cells were identified as main producers of IFNγ in vitro and were found in SG of pSS patients. CONCLUSIONS: IL-33 is released in pSS, and acts with IL-12 and IL-23 to favour the secretion of IFNγ by NK and NKT cells.


Asunto(s)
Interleucinas/metabolismo , Receptores de Superficie Celular/metabolismo , Glándulas Salivales/metabolismo , Síndrome de Sjögren/metabolismo , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Inmunohistoquímica , Interferón gamma/efectos de los fármacos , Interferón gamma/metabolismo , Proteína 1 Similar al Receptor de Interleucina-1 , Interleucina-12/farmacología , Interleucina-17/metabolismo , Interleucina-23/farmacología , Interleucina-33 , Interleucinas/farmacología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/metabolismo , Lupus Eritematoso Sistémico/metabolismo , Masculino , Persona de Mediana Edad , Células T Asesinas Naturales/efectos de los fármacos , Células T Asesinas Naturales/metabolismo , Síndrome de Sjögren/etiología
3.
Dev Cell ; 34(3): 338-50, 2015 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-26190144

RESUMEN

Ciliary transport is required for ciliogenesis, signal transduction, and trafficking of receptors to the primary cilium. Mutations in inositol polyphosphate 5-phosphatase E (INPP5E) have been associated with ciliary dysfunction; however, its role in regulating ciliary phosphoinositides is unknown. Here we report that in neural stem cells, phosphatidylinositol 4-phosphate (PI4P) is found in high levels in cilia whereas phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2) is not detectable. Upon INPP5E inactivation, PI(4,5)P2 accumulates at the ciliary tip whereas PI4P is depleted. This is accompanied by recruitment of the PI(4,5)P2-interacting protein TULP3 to the ciliary membrane, along with Gpr161. This results in an increased production of cAMP and a repression of the Shh transcription gene Gli1. Our results reveal the link between ciliary regulation of phosphoinositides by INPP5E and Shh regulation via ciliary trafficking of TULP3/Gpr161 and also provide mechanistic insight into ciliary alterations found in Joubert and MORM syndromes resulting from INPP5E mutations.


Asunto(s)
Cilios/metabolismo , Proteínas Hedgehog/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Monoéster Fosfórico Hidrolasas/genética , Proteínas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Anomalías Múltiples/genética , Animales , Movimiento Celular/genética , Células Cultivadas , Enfermedades Cerebelosas/genética , Cerebelo/anomalías , AMP Cíclico/biosíntesis , Embrión de Mamíferos/metabolismo , Anomalías del Ojo/genética , Oftalmopatías/genética , Hipocampo/embriología , Discapacidad Intelectual/genética , Péptidos y Proteínas de Señalización Intercelular , Péptidos y Proteínas de Señalización Intracelular , Enfermedades Renales Quísticas/genética , Factores de Transcripción de Tipo Kruppel/biosíntesis , Factores de Transcripción de Tipo Kruppel/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Células-Madre Neurales/metabolismo , Obesidad/genética , Enfermedades del Pene/genética , Fosfatidilinositol 4,5-Difosfato/metabolismo , Transporte de Proteínas/genética , Retina/anomalías , Transducción de Señal , Proteína con Dedos de Zinc GLI1
4.
Front Behav Neurosci ; 5: 47, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21847377

RESUMEN

The striatum, the major input structure of the basal ganglia, is critically involved in motor control and learning of habits and skills, and is also involved in motivational and reward processes. The dorsal striatum, caudate-putamen, is primarily implicated in motor functions whereas the ventral striatum, the nucleus accumbens, is essential for motivation and drug reinforcement. Severe basal ganglia dysfunction occurs in movement disorders as Parkinson's and Huntington's disease, and in psychiatric disorders such as schizophrenia and drug addiction. The striatum is essentially composed of GABAergic medium-sized spiny neurons (MSNs) that are output neurons giving rise to the so-called direct and indirect pathways and are targets of the cerebral cortex and mesencephalic dopaminergic neurons. Although the involvement of striatal sub-areas in motor control and motivation has been thoroughly characterized, major issues remained concerning the specific and respective functions of the two MSNs sub-populations, D(2)R-striatopallidal (dopamine D(2) receptor-positive) and D(1)R-striatonigral (dopamine D(1) receptor-positive) neurons, as well as their specific regulation. Here, we review recent advances that gave new insight in the understanding of the differential roles of striatopallidal and striatonigral neurons in the basal ganglia circuit. We discuss innovative techniques developed in the last decade which allowed a much precise evaluation of molecular pathways implicated in motivational processes and functional roles of striatopallidal and striatonigral neurons in motor control and in the establishment of reward-associated behavior.

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