Perturbations to the IGF1 growth pathway and adult energy homeostasis following disruption of mouse chromosome 12 imprinting

• Published in: Acta Physiologica Vol. 210; no. 1; pp. 174 - 187
• Main Authors: Charalambous, M., da Rocha, S. T., Hernandez, A., Ferguson-Smith, A. C.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.01.2014; Wiley Subscription Services, Inc; John Wiley & Sons Ltd
• Subjects: Aging - genetics; Animals; Base Sequence; Chromosomes, Mammalian - genetics; Energy Metabolism - genetics; Exocrine Pancreatic Insufficiency - genetics; Female; Fetal Growth Retardation - genetics; Genes; Genomic Imprinting - genetics; Glucose - genetics; growth; Homeostasis; Homeostasis - genetics; IGF1 signalling; imprinting; Insulin-Like Growth Factor I - genetics; Insulin-like growth factors; Male; Mice; Mice, Transgenic; Molecular Sequence Data; Mutation - genetics; Rodents; Signal Transduction - genetics; Special Issue: Metabolic Programming (Original ); imprinting; IGF1 signalling; growth
• ISSN: 1748-1708; 1748-1716
• DOI: 10.1111/apha.12160

Aim Disruption to insulin‐like growth factor (IGF) signalling pathways during early life causes growth retardation and defects of developing metabolic organs that can alter set points of energy homeostasis for a lifetime. Inheritance of two maternal copies of human chromosome 14q32.2 (Temple syndrome) causes severe foetal growth retardation and post‐natal failure to thrive. Disruption of imprinted gene dosage in the orthologous region on mouse chromosome 12 also affects growth. Here, we investigated whether altering chromosome 12‐imprinted gene dosage can affect IGF signalling. Methods We investigated mice with a transgene insertion at the imprinted domain of chromosome 12. This lesion causes misexpression of neighbouring genes such that the expression of non‐coding RNAs is elevated, and levels of delta‐like homologue 1 (Dlk1), retrotransposon‐like 1 (Rtl1) and deiodinase 3 (Dio3) transcripts are reduced. Results We observed three key phenotypes in these mice: (i) embryonic growth retardation associated with altered expression of IGF1 binding proteins, (ii) peri‐natal failure to thrive accompanied by hypothyroidism and low serum IGF1. Unexpectedly this phenotype was growth hormone independent. (iii) Adult animals had reduced glucose tolerance as a result of endocrine pancreatic insufficiency. Conclusions We propose that all of these phenotypes are attributable to impaired IGF action and show for the first time that the chromosome 12 cluster in the mouse is an imprinted locus that modulates the IGF signalling pathway. We propose that growth retardation observed in human Temple syndrome might have a similar cause.