Global deficits in development, function, and gene expression in the endocrine pancreas in a deletion mouse model of Prader-Willi syndrome

摘要: Prader-Willi syndrome (PWS) is a multisystem disorder caused by genetic loss of function cluster imprinted, paternally expressed genes. Neonatal failure to thrive in PWS followed childhood-onset hyperphagia and obesity among other endocrine behavioral abnormalities. typically assumed be an unknown hypothalamic-pituitary dysfunction, but the underlying pathogenesis remains unknown. A transgenic deletion mouse model (TgPWS) has severe thrive, with very low levels plasma insulin glucagon fetal neonatal life prior following onset progressive hypoglycemia. In this study, we tested hypothesis that primary deficits pancreatic islet development or may play fundamental role TgPWS phenotype. Major hormones (insulin, glucagon) were decreased mice, consistent levels. Immunohistochemical analysis pancreas demonstrated disrupted morphology islets, reduced α- β-cell mass arising from increase apoptosis. Furthermore, vivo vitro studies show rate secretion significantly impaired β-cells. pancreas, mRNA for genes encoding all hormones, secretory factors, ISL1 transcription factor are upregulated either compensatory response hormone deficiencies effect deleted gene. Our findings identify imprinted required development, survival, coordinate regulation cells, which underlie phenotype model.