The Pathophysiological Basis of Neonatal Failure-to-Thrive in a Prader-Willi Syndrome Mouse Model

Prader-Willi syndrome (PWS) is a multi-system disorder caused by genetic loss of function of several imprinted, paternally-expressed genes. Neonatal failure to thrive is followed by childhood-onset hyperphagia and obesity, among other endocrine and behavioral abnormalities, but the 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.

This study tested the hypothesis that primary deficits in pancreatic islet development or function play a fundamental role in the TgPWS phenotype. Immunohistochemical analysis of the pancreas demonstrated disrupted morphology of TgPWS islets with reduced α- and β-cell mass, arising from an increase in apoptosis. Major hormone contents are moderately decreased in accordance with islet cell mass. Further, in vitro and in vivo studies show that 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 up-regulated either by a compensatory response to plasma hormone deficiencies or a primary effect of a deleted gene.

The study’s findings identified a cluster of imprinted genes required for development, survival, coordination of regulation of genes encoding hormones, and secretory function of pancreatic endocrine cells, which may underlie the neonatal phenotype of the TgPWS mouse model.

Principal Investigator
Robert Nicholls, PhD

Last Update
August 14, 2010
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Last Update
August 14, 2010