title: Ectopic expression of DLK1 protein in skeletal muscle of padumnal heterozygotes causes the callipyge phenotype.
abstract: The callipyge (CLPG) phenotype is an inherited skeletal muscle hypertrophy described in sheep. It is characterized by an unusual mode of inheritance ("polar overdominance") in which only heterozygous individuals having received the CLPG mutation from their father (+(MAT)/CLPG(PAT)) express the phenotype . +(MAT)/CLPG(PAT) individuals are born normal and develop the muscular hypertrophy at approximately 1 month of age. The CLPG mutation was identified as an A to G transition in a highly conserved dodecamer motif located between the imprinted DLK1 and GTL2 genes . This motif is thought to be part of a long-range control element (LRCE) because the CLPG mutation was shown, in postnatal skeletal muscle, to enhance the transcript levels of the DLK1, PEG11, GTL2, and MEG8 genes in cis without altering their imprinting status . As a result, the +(MAT)/CLPG(PAT) individuals have a unique expression profile thought to underlie the callipyge phenotype: an overexpression of the paternally expressed protein encoding DLK1 (Figure 1A) and PEG11 transcripts in the absence of an overexpression of the maternally expressed noncoding GTL2 and MEG8 transcripts . However, the way in which this distinct expression profile causes the callipyge muscular hypertrophy has remained unclear. Herein, we demonstrate that the callipyge phenotype is perfectly correlated with ectopic expression of DLK1 protein in hypertrophied muscle of +(MAT)/CLPG(PAT) sheep. We demonstrate the causality of this association by inducing a generalized muscular hypertrophy in transgenic mice that express DLK1 in skeletal muscle. The absence of DLK1 protein in skeletal muscle of CLPG/CLPG animals, despite the presence of DLK1 mRNA, supports a trans inhibition mediated by noncoding RNAs expressed from the maternal allele.
authors.affiliation: Department of Genetics, Faculty of Veterinary Medicine, University of Liège, B 43 Sart Tilman, Boulevard du Colonster 20, 4000-Liège, Belgium.
authors.forename: Erica
authors.initials: E
authors.lastname: Davis
authors.forename: Charlotte Harken
authors.initials: CH
authors.lastname: Jensen
authors.forename: Henrik Daa
authors.initials: HD
authors.lastname: Schroder
authors.forename: Frédéric
authors.initials: F
authors.lastname: Farnir
authors.forename: Tracy
authors.initials: T
authors.lastname: Shay-Hadfield
authors.forename: Anette
authors.initials: A
authors.lastname: Kliem
authors.forename: Noelle
authors.initials: N
authors.lastname: Cockett
authors.forename: Michel
authors.initials: M
authors.lastname: Georges
authors.forename: Carole
authors.initials: C
authors.lastname: Charlier
mesh_terms: D000818:Animals; D001837:Body Weights and Measures; D017931:DNA Primers; D005260:Female; D015870:Gene Expression; D018392:Genomic Imprinting; D006579:Heterozygote; D006984:Hypertrophy; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D009135:Muscular Diseases / Q000235:genetics / Q000662:veterinary*; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D012044:Regression Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012756:Sheep; D012757:Sheep Diseases / Q000235:genetics*; D019076:Transgenes / Q000235:genetics
chemical_list: D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; C064045:delta protein