In:
PLOS Genetics, Public Library of Science (PLoS), Vol. 16, No. 10 ( 2020-10-15), p. e1009069-
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.
Type of Medium:
Online Resource
ISSN:
1553-7404
DOI:
10.1371/journal.pgen.1009069
DOI:
10.1371/journal.pgen.1009069.g001
DOI:
10.1371/journal.pgen.1009069.g002
DOI:
10.1371/journal.pgen.1009069.g003
DOI:
10.1371/journal.pgen.1009069.g004
DOI:
10.1371/journal.pgen.1009069.g005
DOI:
10.1371/journal.pgen.1009069.g006
DOI:
10.1371/journal.pgen.1009069.s001
DOI:
10.1371/journal.pgen.1009069.s002
DOI:
10.1371/journal.pgen.1009069.s003
DOI:
10.1371/journal.pgen.1009069.s004
DOI:
10.1371/journal.pgen.1009069.s005
DOI:
10.1371/journal.pgen.1009069.s006
DOI:
10.1371/journal.pgen.1009069.s007
DOI:
10.1371/journal.pgen.1009069.s008
DOI:
10.1371/journal.pgen.1009069.s009
DOI:
10.1371/journal.pgen.1009069.s010
DOI:
10.1371/journal.pgen.1009069.s011
DOI:
10.1371/journal.pgen.1009069.s012
DOI:
10.1371/journal.pgen.1009069.s013
DOI:
10.1371/journal.pgen.1009069.s014
DOI:
10.1371/journal.pgen.1009069.s015
DOI:
10.1371/journal.pgen.1009069.s016
DOI:
10.1371/journal.pgen.1009069.s017
DOI:
10.1371/journal.pgen.1009069.r001
DOI:
10.1371/journal.pgen.1009069.r002
DOI:
10.1371/journal.pgen.1009069.r003
DOI:
10.1371/journal.pgen.1009069.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2020
detail.hit.zdb_id:
2186725-2
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