Antagonistic roles in fetal development and adult physiology for the oppositely imprinted Grb10 and Dlk1 genes

BMC Biol. 2014 Dec 31;12:771. doi: 10.1186/s12915-014-0099-8.

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.

Publication types

  • Historical Article
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Absorptiometry, Photon
  • Adipose Tissue / metabolism
  • Animals
  • Calcium-Binding Proteins
  • Cell Proliferation
  • Female
  • Fetal Development / genetics*
  • Fibroblasts / metabolism
  • G2 Phase
  • GRB10 Adaptor Protein / genetics*
  • GRB10 Adaptor Protein / metabolism
  • Genomic Imprinting*
  • Glucose Tolerance Test
  • History, Ancient
  • Insulin-Like Growth Factor II / genetics
  • Insulin-Like Growth Factor II / metabolism
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Organ Size
  • S Phase
  • Triglycerides / blood

Substances

  • Calcium-Binding Proteins
  • Dlk1 protein, mouse
  • Grb10 protein, mouse
  • IGF2 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Triglycerides
  • GRB10 Adaptor Protein
  • Insulin-Like Growth Factor II