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.
Highlights
The mammalian pancreas plays a central role in energy homeostasis, which is achieved by functionally and morphologically distinct exocrine and endocrine components
The pancreas is formed of two main components: the exocrine pancreas and the endocrine pancreas
In this study, using mouse genetic engeneering, we explored the roles played by a hormone-like gene called insulin-like growth factor 2 (Igf2), that is similar in structure to insulin, and is active only on the chromosome inherited from the father
Summary
The mammalian pancreas plays a central role in energy homeostasis, which is achieved by functionally and morphologically distinct exocrine and endocrine components. The size of the pancreas is thought to be fixed early in development, limited by the size of the progenitor cell pool that is established in the developing pancreatic bud [1]. Mesenchymal cells overlie the developing pancreatic bud and provide critical signals for the expansion of both precursors and differentiated endocrine and exocrine cells [2]. These cells are present throughout pancreas organogenesis, but the relative proportion of mesenchyme to epithelium changes, with a dramatic reduction over time, as the mesenchyme differentiates into more specialized cell types such as pericytes [3] and epithelial cells expand. The factors required for cell fate decisions that specify individual pancreas cell type subsets are fairly well established but less is known about signalling pathways involved in proliferation and survival of cell types
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