title: Antagonistic roles in fetal development and adult physiology for the oppositely imprinted Grb10 and Dlk1 genes.
abstract: BACKGROUND
  Despite being a fundamental biological problem the control of body size and proportions during development remains poorly understood, although it is accepted that the insulin-like growth factor (IGF) pathway has a central role in growth regulation, probably in all animals. The involvement of imprinted genes has also attracted much attention, not least because two of the earliest discovered were shown to be oppositely imprinted and antagonistic in their regulation of growth. The Igf2 gene encodes a paternally expressed ligand that promotes growth, while maternally expressed Igf2r encodes a cell surface receptor that restricts growth by sequestering Igf2 and targeting it for lysosomal degradation. There are now over 150 imprinted genes known in mammals, but no other clear examples of antagonistic gene pairs have been identified. The delta-like 1 gene (Dlk1) encodes a putative ligand that promotes fetal growth and in adults restricts adipose deposition. Conversely, Grb10 encodes an intracellular signalling adaptor protein that, when expressed from the maternal allele, acts to restrict fetal growth and is permissive for adipose deposition in adulthood.
  
  
  RESULTS
  Here, using knockout mice, we present genetic and physiological evidence that these two factors exert their opposite effects on growth and physiology through a common signalling pathway. The major effects are on body size (particularly growth during early life), lean:adipose proportions, glucose regulated metabolism and lipid storage in the liver. A biochemical pathway linking the two cell signalling factors remains to be defined.
  
  
  CONCLUSIONS
  We propose that Dlk1 and Grb10 define a mammalian growth axis that is separate from the IGF pathway, yet also features an antagonistic imprinted gene pair.
authors.forename: Marta
authors.initials: M
authors.lastname: Madon-Simon
authors.forename: Michael
authors.initials: M
authors.lastname: Cowley
authors.forename: Alastair S
authors.initials: AS
authors.lastname: Garfield
authors.forename: Kim
authors.initials: K
authors.lastname: Moorwood
authors.forename: Steven R
authors.initials: SR
authors.lastname: Bauer
authors.affiliation: Department of Biology & Biochemistry and Centre for Regenerative Medicine, University of Bath, Building 4 South, Claverton Down, Bath BA2 7AY, UK. bssaw@bath.ac.uk.
authors.forename: Andrew
authors.initials: A
authors.lastname: Ward
mesh_terms: D015502:Absorptiometry, Photon; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002135:Calcium-Binding Proteins; D049109:Cell Proliferation; D005260:Female; D047109:Fetal Development / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism; D016195:G2 Phase; D051383:GRB10 Adaptor Protein / Q000235:genetics* / Q000378:metabolism; D018392:Genomic Imprinting; D005951:Glucose Tolerance Test; D049690:History, Ancient; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size; D016196:S Phase; D014280:Triglycerides / Q000097:blood
chemical_list: D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; C495959:Grb10 protein, mouse; C513121:IGF2 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D014280:Triglycerides; D051383:GRB10 Adaptor Protein; D007335:Insulin-Like Growth Factor II