Asunto(s)
Cromosomas Humanos X/genética , Proteínas de Unión al ADN/genética , Duplicación de Gen , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Proteínas del Grupo de Alta Movilidad/genética , Hipopituitarismo/genética , Hibridación de Ácido Nucleico , Análisis de Secuencia por Matrices de Oligonucleótidos , Factores de Transcripción/genética , Cromosomas Artificiales Bacterianos/genética , Cromosomas Humanos X/ultraestructura , Genes Ligados a X , Humanos , Masculino , Hibridación de Ácido Nucleico/métodos , Reacción en Cadena de la Polimerasa , Reproducibilidad de los Resultados , Factores de Transcripción SOXB1 , Método Simple CiegoRESUMEN
Normal pituitary gland development requires coordination between maintenance of progenitor cell pools and selection of progenitors for differentiation. The spatial and temporal expression of Notch2 during pituitary development suggested that it could control progenitor cell differentiation in the pituitary. Consistent with this idea, Notch2 is not expressed in Prop1 mutants, and anterior pituitary progenitors in Prop1 mutants appear to be unable to transition from proliferation to differentiation properly, resulting in anterior lobe failed cell specification and evolving hypoplasia. To test the function of Notch2 directly, we used the alphaGSU subunit promoter to express activated NOTCH2 persistently in pre-gonadotropes and pre-thyrotropes of transgenic mice. At birth, there is a small reduction in the population of fully differentiated thyrotropes and almost no fully differentiated gonadotropes. The temporal and spatial expression of Hey1 suggests that it could be a mediator of this effect. Gonadotropes complete their differentiation program eventually, although expression of LH and FSH is mutually exclusive with NOTCH2 transgene expression. This demonstrates that activated Notch2 is sufficient to delay gonadotrope differentiation, and it supports the hypothesis that Notch2 regulates progenitor cell differentiation in the pituitary gland.
Asunto(s)
Diferenciación Celular/fisiología , Gonadotrofos/metabolismo , Gonadotrofos/fisiología , Receptor Notch2/metabolismo , Animales , Linaje de la Célula , Embrión de Mamíferos/metabolismo , Femenino , Regulación del Desarrollo de la Expresión Génica , Hormonas Glicoproteicas de Subunidad alfa/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Hipófisis/embriología , Hipófisis/metabolismo , Proopiomelanocortina/metabolismo , Tirotrofos/metabolismo , Tirotropina/metabolismo , TransgenesRESUMEN
The genetic basis of a number of epilepsy syndromes has been identified but the precise mechanism whereby these mutations produce seizures is unknown. Three mutations of the alpha(4) subunit of the neuronal nicotinic acetylcholine receptor (nAChR) have been identified in autosomal dominant nocturnal frontal lobe epilepsy. In vitro studies of two mutations suggest an alteration of receptor function resulting in decreased ion channel current flow. We investigated the response of alpha(4) nAChR subunit knockout mice to the gamma-aminobutyric acid (GABA) receptor antagonists; pentylenetetrazole (PTZ) and bicuculline (BIC), the glutamate receptor agonist kainic acid (KA), the glycine receptor antagonist strychnine and the K(+) channel blocker 4-aminopyridine (4-AP). Mutant (Mt) mice had a greater sensitivity to PTZ and BIC, with an increase in major motor seizures and seizure-related deaths. Furthermore, Mt mice were more sensitive to KA and strychnine, but the effects were much smaller compared to those seen with the GABA receptor antagonists. Paradoxically, Mt mice appeared to be relatively protected from 4-AP-induced major motor seizures and death. The results show that a functional deletion of the alpha(4) nAChR subunit in vivo is associated with a major increase in sensitivity to GABA receptor blockers.
