Mesenchyme-derived IGF2 is a major paracrine regulator of pancreatic growth and function


Autoři: Constanze M. Hammerle aff001;  Ionel Sandovici aff001;  Gemma V. Brierley aff001;  Nicola M. Smith aff001;  Warren E. Zimmer aff004;  Ilona Zvetkova aff001;  Haydn M. Prosser aff005;  Yoichi Sekita aff001;  Brian Y. H. Lam aff001;  Marcella Ma aff001;  Wendy N. Cooper aff001;  Antonio Vidal-Puig aff001;  Susan E. Ozanne aff001;  Gema Medina-Gómez aff006;  Miguel Constância aff001
Působiště autorů: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Institute of Metabolic Science, Addenbrookes Hospital, Cambridge, United Kingdom aff001;  Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom aff002;  Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom aff003;  Department of Medical Physiology, Texas A&M Health Science Center, College Station, Texas, United States of America aff004;  The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, United Kingdom aff005;  Área de Bioquímica y Biología Molecular, Departamento de Ciencias Básicas de la Salud, Universidad Rey Juan Carlos, 28922-Alcorcón, Madrid, Spain aff006
Vyšlo v časopise: Mesenchyme-derived IGF2 is a major paracrine regulator of pancreatic growth and function. PLoS Genet 16(10): e32767. doi:10.1371/journal.pgen.1009069
Kategorie: Research Article
doi: 10.1371/journal.pgen.1009069

Souhrn

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.

Klíčová slova:

Alleles – Body weight – Gene expression – Genetically modified animals – Mouse models – Pancreas – Polymerase chain reaction – Pregnancy


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