RT Journal Article
SR Electronic
T1 Mesenchymal <em>Igf2</em> is a major paracrine regulator of pancreatic growth and function
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 714121
DO 10.1101/714121
A1 Constanze M. Hammerle
A1 Ionel Sandovici
A1 Gemma V. Brierley
A1 Nicola M. Smith
A1 Warren E. Zimmer
A1 Ilona Zvetkova
A1 Haydn M. Prosser
A1 Yoichi Sekita
A1 Brian Y.H. Lam
A1 Marcella Ma
A1 Wendy N. Cooper
A1 Antonio Vidal-Puig
A1 Susan E. Ozanne
A1 Gema Medina-Gómez
A1 Miguel Constância
YR 2019
UL http://biorxiv.org/content/early/2019/07/31/714121.abstract
AB 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.