RESUMEN
Insulin from the beta-cells of the pancreatic islets of Langerhans controls energy homeostasis in vertebrates, and its deficiency causes diabetes mellitus. During embryonic development, the transcription factor neurogenin 3 (Neurog3) initiates the differentiation of the beta-cells and other islet cell types from pancreatic endoderm, but the genetic program that subsequently completes this differentiation remains incompletely understood. Here we show that the transcription factor Rfx6 directs islet cell differentiation downstream of Neurog3. Mice lacking Rfx6 failed to generate any of the normal islet cell types except for pancreatic-polypeptide-producing cells. In human infants with a similar autosomal recessive syndrome of neonatal diabetes, genetic mapping and subsequent sequencing identified mutations in the human RFX6 gene. These studies demonstrate a unique position for Rfx6 in the hierarchy of factors that coordinate pancreatic islet development in both mice and humans. Rfx6 could prove useful in efforts to generate beta-cells for patients with diabetes.
Asunto(s)
Diferenciación Celular , Proteínas de Unión al ADN/metabolismo , Insulina/biosíntesis , Islotes Pancreáticos/citología , Islotes Pancreáticos/metabolismo , Factores de Transcripción/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/deficiencia , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Análisis Mutacional de ADN , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Diabetes Mellitus/congénito , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patología , Embrión de Mamíferos/metabolismo , Femenino , Feto/metabolismo , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Genes Recesivos/genética , Pruebas Genéticas , Humanos , Recién Nacido , Islotes Pancreáticos/embriología , Masculino , Ratones , Células 3T3 NIH , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Especificidad de Órganos , Factores de Transcripción del Factor Regulador X , Síndrome , Factores de Transcripción/deficiencia , Factores de Transcripción/genéticaRESUMEN
The earliest endocrine cells in the developing pancreas make glucagon and are described as alpha cells. We show here that these cells express islet amyloid polypeptide and prohormone convertase 1/3 (PC1/3), proteins that are not expressed by mature alpha cells, but are found in beta cells. PC1/3 converts proglucagon to the functionally distinct hormones glucagon-like peptide (GLP)-1 and GLP-2 rather than glucagon. Despite these differences, the early proglucagon-positive cells express, as do mature alpha cells, the POU domain transcription factor Brn-4, and do not express the beta cell factor pdx-1. The early production of atypical peptide hormones by these cells suggests that they could play an important role locally or systemically in the development of the embryo.