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Perturbations to the IGF 1 growth pathway and adult energy homeostasis following disruption of mouse chromosome 12 imprinting
Author(s) -
Charalambous M.,
da Rocha S. T.,
Hernandez A.,
FergusonSmith A. C.
Publication year - 2014
Publication title -
acta physiologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.591
H-Index - 116
eISSN - 1748-1716
pISSN - 1748-1708
DOI - 10.1111/apha.12160
Subject(s) - biology , genomic imprinting , imprinting (psychology) , endocrinology , growth factor , glucose homeostasis , medicine , transgene , locus (genetics) , genetics , microbiology and biotechnology , gene , gene expression , receptor , insulin , dna methylation , insulin resistance
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 ( T emple 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 RNA s is elevated, and levels of delta‐like homologue 1 ( D lk1 ), retrotransposon‐like 1 ( R tl1 ) and deiodinase 3 ( D io3 ) transcripts are reduced. Results We observed three key phenotypes in these mice: (i) embryonic growth retardation associated with altered expression of IGF 1 binding proteins, (ii) peri‐natal failure to thrive accompanied by hypothyroidism and low serum IGF 1. 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 T emple syndrome might have a similar cause.