Global deficits in development, function, and gene expression in the endocrine pancreas in a deletion mouse model of
Mihaela Stefan1, Rebecca A Simmons, Suzanne Bertera
1Dept. of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Rangos Research Bldg., 4401 Penn Ave., Pittsburgh, PA 15224, USA.
Insights
Prader-Willi syndrome (PWS) involves genetic defects affecting pancreatic islet cells, leading to hormone deficiencies and impaired insulin secretion in newborns. This study reveals critical roles for imprinted genes in pancreatic development and function.
Area of Science:
- Endocrinology
- Developmental Biology
- Genetics
Background:
- Prader-Willi syndrome (PWS) is a genetic disorder characterized by multisystem dysfunction, including neonatal failure to thrive and later hyperphagia and obesity.
- The underlying pathogenesis of PWS, particularly neonatal issues, is poorly understood, with current hypotheses focusing on hypothalamic-pituitary dysfunction.
Purpose of the Study:
- To investigate the role of pancreatic islet development and function in the neonatal phenotype of a transgenic mouse model of Prader-Willi syndrome (TgPWS).
- To determine if primary deficits in pancreatic islet cells contribute to the failure to thrive observed in neonatal TgPWS mice.
Main Methods:
- Analysis of plasma insulin and glucagon levels in TgPWS mice.
- Immunohistochemical examination of pancreatic islet morphology, including α- and β-cell mass and apoptosis.
- In vivo and in vitro assessment of insulin secretion from TgPWS β-cells.
- Quantification of mRNA levels for pancreatic hormone genes and the ISL1 transcription factor in TgPWS pancreas.
Main Results:
- TgPWS mice exhibited decreased pancreatic islet hormones (insulin, glucagon) and disrupted islet morphology with reduced α- and β-cell mass due to increased apoptosis.
- Impaired insulin secretion was observed in TgPWS β-cells.
- Upregulation of genes encoding pancreatic hormones, secretory factors, and ISL1 was noted in the TgPWS pancreas.
Conclusions:
- A cluster of imprinted genes is essential for the development, survival, and secretory function of pancreatic endocrine cells.
- Deficits in pancreatic islet development and function, driven by imprinted gene loss, likely underlie the neonatal failure to thrive phenotype in the TgPWS mouse model.
- These findings highlight a novel contribution of pancreatic islet dysfunction to Prader-Willi syndrome pathogenesis.
Abstract:
Prader-Willi syndrome (PWS) is a multisystem disorder caused by genetic loss of function of a cluster of imprinted, paternally expressed genes. Neonatal failure to thrive in PWS is followed by childhood-onset hyperphagia and obesity among other endocrine and behavioral abnormalities. PWS is typically assumed to be caused by an unknown hypothalamic-pituitary dysfunction, but the underlying pathogenesis remains unknown. A transgenic deletion mouse model (TgPWS) has severe failure to thrive, with very low levels of plasma insulin and glucagon in fetal and neonatal life prior to and following onset of progressive hypoglycemia. In this study, we tested the hypothesis that primary deficits in pancreatic islet development or function may play a fundamental role in the TgPWS neonatal phenotype. Major pancreatic islet hormones (insulin, glucagon) were decreased in TgPWS mice, consistent with plasma levels. Immunohistochemical analysis of the pancreas demonstrated disrupted morphology of TgPWS islets, with reduced α- and β-cell mass arising from an increase in apoptosis. Furthermore, in vivo and in vitro studies show that the rate of insulin secretion is significantly impaired in TgPWS β-cells. In TgPWS pancreas, mRNA levels for genes encoding all pancreatic hormones, other secretory factors, and the ISL1 transcription factor are upregulated by either a compensatory response to plasma hormone deficiencies or a primary effect of a deleted gene. Our findings identify a cluster of imprinted genes required for the development, survival, coordinate regulation of genes encoding hormones, and secretory function of pancreatic endocrine cells, which may underlie the neonatal phenotype of the TgPWS mouse model.
