The endocrine pancreas undergoes major remodeling during neonatal development when replication of differentiated β cells is the major mechanism by which β cell mass is regulated. The molecular mechanisms that govern the replication of terminally differentiated β cells are unclear. We show that during neonatal development, cyclin D2 expression in the endocrine pancreas coincides with the replication of endocrine cells and a massive increase in islet mass. Using cyclin D2 -/-mice, we demonstrate that cyclin D2 is required for the replication of endocrine cells but is expendable for exocrine and ductal cell replication. As a result, 14-day-old cyclin D2 -/-mice display dramatically smaller islets and a 4-fold reduction in β cell mass in comparison to their WT littermates. Consistent with these morphological findings, the cyclin D2 -/-mice are glucose intolerant. These results suggest that cyclin D2 plays a key role in regulating the transition of β cells from quiescence to replication and may provide a target for the development of therapeutic strategies to induce expansion and/or regeneration of β cells. IntroductionThe β cell mass plays an essential role in determining the amount of insulin that is secreted to maintain the body's glucose levels within a narrow range. Increasing evidence suggests that the β cell mass is dynamic and variations in insulin demand can lead to rapid and marked changes in the β cell mass (1-3). The mass of β cells is governed by balancing β cell growth (differentiation and replication) and β cell death (apoptosis). The molecular basis of the parameters regulating β cell mass are not clear (4). Understanding the regulation of β cell mass is especially important because the inability of the endocrine pancreas to compensate for the changing insulin demand can contribute to the pathogenesis of diabetes (5-7).During mouse embryogenesis, β cells are generated from a population of pancreatic progenitor cells (8,9). The β cells that differentiate from progenitor cells are postmitotic, and direct lineage tracing analyses indicate that a population of progenitor cells persists throughout embryogenesis to allow the differentiation of new β cells (10, 11). During postnatal development, however, replication of differentiated β cells can lead to addition of new β cells (12). High rates of β cell replication during the neonatal period results in a massive increase in β cell mass (13,14). How do terminally differentiated β cells transition between quiescence to replication in the neonatal period? Here we examine the role of D-cyclins in regulating cell cycle progression of β cells in postnatal development. The three D-cyclins (cyclins D1, D2, and D3) are key components of the cell cycle machinery encoded by separate genes, but show significant homology at the protein level (15). The levels of D-cyclins are controlled by mitogens and, upon induction, associate with partner cyclin-dependent kinases CDK4 and CDK6 to drive cells into S-phase (16, 17). Here we report that one D-cyclin, cyclin D2, is uniquel...
Summary Adult pancreatic beta cells can replicate during growth and after injury to maintain glucose homeostasis. Here we report that beta cells deficient in Dnmt1, an enzyme that propagates DNA methylation patterns during cell division, were converted to alpha cells. We identified the lineage determination gene aristaless related homeobox (Arx), as methylated and repressed in beta cells, and hypo-methylated and expressed in alpha cells and Dnmt1-deficient beta cells. We show that the methylated region of the Arx locus in beta cells was bound by methyl binding protein MeCP2 which recruited PRMT6, an enzyme that methylates histone H3R2 resulting in repression of Arx. This suggests that propagation of DNA methylation during cell division also ensures recruitment of enzymatic machinery capable of modifying and transmitting histone marks. Our results reveal that propagation of DNA methylation during cell division is essential for repression of alpha cell lineage determination genes to maintain pancreatic beta cell identity.
Background & Aims Proprotein convertase 1/3 (PC1/3) deficiency, an autosomal recessive disorder caused by rare mutations in the PCSK1 gene, has been associated with obesity, severe malabsorptive diarrhea, and certain endocrine abnormalities. Common variants in PCSK1 have also been associated with obesity in heterozygotes in several population studies. PC1/3 is an endoprotease that processes many prohormones expressed in endocrine and neuronal cells. We investigated clinical and molecular features of PC1/3 deficiency. Methods We studied the clinical features of 13 children with PC1/3 deficiency and performed sequence analysis of PCSK1. We measured enzymatic activity of recombinant PC1/3 proteins. Results We identified a pattern of endocrinopathies that develop in an age-dependent manner. Eight of the mutations had severe biochemical consequences in vitro. Neonates had severe malabsorptive diarrhea and failure to thrive, required prolonged parenteral nutrition support, and had high mortality. Additional endocrine abnormalities developed as the disease progressed, including diabetes insipidus, growth hormone deficiency, primary hypogonadism, adrenal insufficiency, and hypothyroidism. We identified growth hormone deficiency, central diabetes insipidus, and male hypogonadism as new features of PCSK1 insufficiency. Interestingly, despite early growth abnormalities, moderate obesity, associated with severe polyphagia, generally appears. Conclusion In a study of 13 children with PC1/3 deficiency caused by disruption of PCSK1, failure of enteroendocrine cells to produce functional hormones resulted in generalized malabsorption. These findings indicate that PC1/3 is involved in processing of one or more enteric hormones that are required for nutrient absorption.
In developing organs, the regulation of cell proliferation and cell cycle exit is coordinated. How this coordination is achieved, however, is not clear. We show that the cyclin kinase inhibitor p57 regulates cell cycle exit of progenitors during the early stages of pancreas formation. In the absence of p57, the number of cycling progenitors increases, although expansion of progenitor population is prevented by apoptosis. We report that p57 is a direct target of transcriptional repression by Notch effector, Hes1. Inactivation of Hes1 results in the upregulation of p57 expression in progenitors, leading to cell cycle arrest, precocious differentiation and depletion of the progenitor pool. We present evidence that in p57/Hes1 double null embryos, the absence of apoptosis results in the expansion of the progenitor population. We propose that Hes1 and p57 not only coordinate cell cycle exit and self-renewal of pancreatic progenitors during an early stage in organogenesis to regulate the number of pancreatic progenitors, but could also constitute a surveillance system to eliminate cells with aberrant cell cycle characteristics.
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