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

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.

Calorie seeking, but not hedonic response, contributes to hyperphagia in a mouse model for Prader–Willi syndrome

“…Here the suggestion is not that these animals are more sensitive to calories but, as sweet taste may guide ingestion by acting as a Pavlovian cue that signals ensuing metabolic consequences, glucoprivation removes a critical physiological signal involved in the control of goal‐directed sweetener intake (Tellez et al ., ). Although not measured directly here, a Tg‐PWS mouse model, which shows global loss of PWS gene expression like the PWS ICdel mice (Relkovic & Isles, ), has both hypoglycaemia (Stefan et al ., ) and hypoinsulinaemia (Stefan et al ., ). It is reasonable to suggest that the PWS ICdel mice would display a similar metabolic phenotype, which in turn supports the idea that their altered basal physiology impacts on their response to saccharin.…”

Appetite hormones and the transition to hyperphagia in children with Prader-Willi syndrome

“…Interestingly, PWS genes are expressed in the mouse pancreas, and a mouse deletion model of PWS displays low embryonic and neonatal insulin and glucagon levels, impaired b-cell insulin secretion, reduced a-and b-cell mass with increased apoptosis and upregulation of mRNA for pancreatic insulin, glucagon, PP and other secretory factors. 57 However, plasma PP levels have not been reported in PWS mouse models.…”

Phenotypic Outcomes of Imprinted Gene Models in Mice: Elucidation of Pre- and Postnatal Functions of Imprinted Genes

“…At postnatal day 3 (P3), pups have altered levels of the appetite regulators AgrP and α-MSH, resulting in reduced appetite (73), hypoglycemia, and increased fat metabolism (192). These animals also have decreased α and β cells in the pancreas, leading to a reduction in insulin (193). A smaller paternal deletion between Snrpn and Ube3a also leads to growth retardation, hypotonia, and neonatal death, suggesting that Ndn, Magel2, Mkrn3, and Frat3 are not major contributors to the neonatal failure-to-thrive phenotype (213).…”