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- Title
Mesenchyme-derived IGF2 is a major paracrine regulator of pancreatic growth and function.
- Authors
Hammerle, Constanze M.; Sandovici, Ionel; Brierley, Gemma V.; Smith, Nicola M.; Zimmer, Warren E.; Zvetkova, Ilona; Prosser, Haydn M.; Sekita, Yoichi; Lam, Brian Y. H.; Ma, Marcella; Cooper, Wendy N.; Vidal-Puig, Antonio; Ozanne, Susan E.; Medina-Gómez, Gema; Constância, Miguel
- Abstract
The genetic mechanisms that determine the size of the adult pancreas are poorly understood. Imprinted genes, which are expressed in a parent-of-origin-specific manner, are known to have important roles in development, growth and metabolism. However, our knowledge regarding their roles in the control of pancreatic growth and function remains limited. Here we show that many imprinted genes are highly expressed in pancreatic mesenchyme-derived cells and explore the role of the paternally-expressed insulin-like growth factor 2 (Igf2) gene in mesenchymal and epithelial pancreatic lineages using a newly developed conditional Igf2 mouse model. Mesenchyme-specific Igf2 deletion results in acinar and beta-cell hypoplasia, postnatal whole-body growth restriction and maternal glucose intolerance during pregnancy, suggesting that the mesenchyme is a developmental reservoir of IGF2 used for paracrine signalling. The unique actions of mesenchymal IGF2 are demonstrated by the absence of any discernible growth or functional phenotypes upon Igf2 deletion in the developing pancreatic epithelium. Additionally, increased IGF2 levels specifically in the mesenchyme, through conditional Igf2 loss-of-imprinting or Igf2r deletion, leads to pancreatic acinar overgrowth. Furthermore, ex-vivo exposure of primary acinar cells to exogenous IGF2 activates AKT, a key signalling node, and increases their number and amylase production. Based on these findings, we propose that mesenchymal Igf2, and perhaps other imprinted genes, are key developmental regulators of adult pancreas size and function. Author summary: The pancreas is formed of two main components: the exocrine pancreas (producing digestive enzymes that break down food so it can be easily absorbed by the intestine) and the endocrine pancreas (producing insulin and other hormones that control blood sugar levels). Additionally, the pancreas contains stromal cells (mesenchyme-derived cells) that support the function of the exocrine and endocrine components. We know little about how the pancreas reaches its normal size. In this study, using mouse genetic engeneering, we explored the roles played by a hormone-like gene called Igf2, that is similar in structure to insulin, and is active only on the chromosome inherited from the father. We found that within the pancreas, Igf2 is mostly active in the mesenchyme-derived cells. When Igf2 is lost specifically within these cells, the entire pancreas becomes smaller, with reduced capacity to produce digestive enzymes and to maintain normal blood sugar levels during pregnancy. Increased IGF2 levels in the mesenchyme-derived cells leads to a larger pancreas, while no effects are observed when Igf2 is lost in the exocrine and endocrine pancreas. Our results demonstrate that Igf2 activity in mesenchyme-derived cells is key for the control of pancreas size and function.
- Subjects
SOMATOMEDIN A; PANCREAS; GROWTH regulators; ISLANDS of Langerhans; ENTEROENDOCRINE cells; BLOOD sugar; IMPRINTED polymers
- Publication
PLoS Genetics, 2020, Vol 16, Issue 10, p1
- ISSN
1553-7390
- Publication type
Article
- DOI
10.1371/journal.pgen.1009069