Hammerle, Constanze M.Sandovici, IonelBrierley, Gemma V.Smith, Nicola M.Zimmer, Warren E.Zvetkova, lonaProsser, Haydn M.Sekita, YoichiLam, Brian Y. H.Ma, MarcellaCooper, Wendy N.Vidal-Puig, AntonioOzanne, Susan E.Medina-Gomez, GemaConstancia, Miguel2023-12-192023-12-192020-10-15Hammerle CM, Sandovici I, Brierley GV, Smith NM, Zimmer WE, Zvetkova I, Prosser HM, Sekita Y, Lam BYH, Ma M, Cooper WN, Vidal-Puig A, Ozanne SE, Medina-Gómez G, Constância M. Mesenchyme-derived IGF2 is a major paracrine regulator of pancreatic growth and function. PLoS Genet. 2020 Oct 15;16(10):e1009069. doi: 10.1371/journal.pgen.1009069. PMID: 33057429; PMCID: PMC7678979.1553-7404https://hdl.handle.net/10115/27474The 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.engAttribution 4.0 Internationalhttps://creativecommons.org/licenses/by/4.0/Acinar Cells / metabolism Acinar Cells / pathology Amino Acids / genetics Animals Cell Lineage / genetics Chromium DNA Methylation / genetics Female Flow Cytometry Gene Expression Regulation, Developmental / genetics Genomic Imprinting / genetics Insulin-Like Growth Factor II / genetics* Insulin-Secreting Cells / metabolism Insulin-Secreting Cells / pathology Mesoderm / growth & development* Mice Nicotinic Acids / genetics Pancreas / cytology Pancreas / growth & development* Pancreas / metabolism Paracrine Communication / genetics* Pregnancy RNA, Long Noncoding / geneticsinfo:eu-repo/semantics/article10.1371/journal.pgen.1009069info:eu-repo/semantics/openAccess