MesenchymalIgf2is a major paracrine regulator of pancreatic growth and function

Abstract

The genetic mechanisms that determine the size of the adult pancreas are poorly understood. Here we demonstrate that many imprinted genes are highly expressed in the pancreatic mesenchyme, and explore the role of Igf2 in-vivo. Mesenchyme-specific Igf2 deletion results in acinar and beta-cell hypoplasia, postnatal whole-body growth restriction and maternal glucose intolerance during pregnancy. Surprisingly, mesenchymal mass is unaffected, 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 phenotypes upon Igf2 deletion in the developing pancreatic epithelium. Furthermore, increased IGF2 activity specifically in the mesenchyme, through Igf2 loss-of-imprinting or Igf2r deletion, leads to pancreatic acinar overgrowth. Ex-vivo exposure of primary acinar cells to exogenous IGF2 increases cell proliferation and amylase production through AKT signalling. We propose that mesenchymal Igf2, and perhaps other imprinted genes, are key developmental regulators of adult pancreas size and function.

Hepatocyte Deletion of IGF2 Prevents DNA Damage and Tumor Formation in Hepatocellular Carcinoma

“…[ 3a ] Igf2 floxed mouse containing loxP sites on either side of exons 4–6 were obtained from Dr. Miguel Costancia, University of Cambridge. [ 48 ] A hepatocyte‐specific double deletion of SRSF3 and IGF2 (DKO), or single IGF2 deletion (IGKO) mice was generated by breeding Igf2 fl:fl mice with the SKO ( Srsf3 fl/fl :Alb‐cre ) mice to generate DKO ( Igf2 fl/fl :Srsf3 fl/fl :Alb‐cre ) and IGKO ( Igf2 fl/fl :Alb‐cre ) mice. Hepatocyte‐specific SRSF1 knockout mice were generated by crossing Srsf1 ‐floxed mice to the Alb‐Cre mice as described for the Srsf3 mice.…”