RESUMEN
The basic helix-loop-helix transcription factor NeuroD1 regulates cell fate in the nervous system but previously has not been considered to function similarly in the endocrine pancreas due to its reported expression in all islet cell types in the newborn mouse. Because we found that NeuroD1 potently represses somatostatin expression in vitro, its pattern of expression was examined in both strains of mice in which lacZ has been introduced into the NeuroD1 locus by homologous recombination. Analysis of adult transgenic mice revealed that NeuroD1 is predominantly expressed in beta-cells and either absent or expressed below the limit of lacZ detection in mature alpha-, delta-, or PP cells. Consistent with a previous report, NeuroD1 colocalizes with glucagon as well as insulin in immature islets of the newborn mouse. However, no colocalization of NeuroD1with somatostatin was detected in the newborn. In vitro, ectopic expression of NeuroD1 in TRM-6/PDX-1, a human pancreatic delta-cell line, resulted in potent repression of somatostatin concomitant with induction of the beta-cell hormones insulin and islet amyloid polypeptide. Additionally, NeuroD1 induced expression of Nkx2.2, a transcription factor expressed in beta- but not delta-cells. Transfection studies using insulin and somatostatin promoters confirm the ability of NeuroD1 to act as both a transcriptional repressor and activator in the same cell, suggesting a more complex role for NeuroD1 in the establishment and/or maintenance of mature endocrine cells than has been recognized previously.
Asunto(s)
Perfilación de la Expresión Génica , Proteínas del Tejido Nervioso/metabolismo , Páncreas/metabolismo , Proteínas Represoras/metabolismo , Transactivadores/metabolismo , Envejecimiento/fisiología , Amiloide/metabolismo , Animales , Animales Recién Nacidos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Línea Celular , ADN/metabolismo , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Proteína Homeobox Nkx-2.2 , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Insulina/genética , Islotes Pancreáticos/citología , Islotes Pancreáticos/metabolismo , Ratones , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares , Páncreas/citología , Páncreas/crecimiento & desarrollo , Regiones Promotoras Genéticas/genética , Estructura Terciaria de Proteína , Proteínas Represoras/química , Proteínas Represoras/genética , Somatostatina/genética , Somatostatina/metabolismo , Transactivadores/química , Transactivadores/genética , Factores de Transcripción/metabolismo , Transcripción Genética/genética , Proteínas de Pez CebraRESUMEN
Because of their localization at the interface between blood and tissue, endothelial cells are responsible for the maintenance of vascular homeostasis. They fulfil a series of various functions and constantly interact with circulating leukocytes and with the smooth muscle cells (SMC) present in the media. Any disturbance of their metabolism can thus lead to alterations of the blood vessel functions. We have shown that hypoxia, for example resulting from venous stasis, induces the activation of endothelial cells which then release inflammatory mediators able to activate neutrophils and to induce their infiltration as well as growth factors for SMC. We propose that these processes are the beginning of a cascade of events eventually leading to structural and functional modifications of the venous wall similar to the ones observed in varicose vein wall. The endothelium alterations resulting from venous stasis would thus be the origin of the development of the venous disease. Pharmacological and clinical evidence reinforce this hypothesis.