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

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.