Abstract
BackgroundDespite 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.ResultsHere, 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.ConclusionsWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-014-0099-8) contains supplementary material, which is available to authorized users.
Highlights
Despite being a fundamental biological problem the control of body size and proportions during development remains poorly understood, it is accepted that the insulin-like growth factor (IGF) pathway has a central role in growth regulation, probably in all animals
To investigate growth phenotypes resulting from ablation of the growth factor receptor-bound protein 10 (Grb10) and delta-like 1 gene (Dlk1) genes, fetal and placental wet weights together with placental efficiencies were analysed at different gestational stages (Figure 1 and Additional file 1: Figure S1)
At embryonic day (E)12.5 Grb10m/+and Grb10m/+/Dlk1+/p fetuses were significantly heavier than wild type and Dlk1+/p littermate controls, with no statistically significant differences seen in placental mass
Summary
Despite being a fundamental biological problem the control of body size and proportions during development remains poorly understood, it is accepted that the insulin-like growth factor (IGF) pathway has a central role in growth regulation, probably in all animals. There is a wealth of information about the underlying cellular processes, including the regulation of cell survival, proliferation and differentiation, but the control of growth and proportions at the level of tissues, organs and body size remains poorly understood [1,2,3,4,5]. ? 2014 Madon-Simon et al.; licensee BioMed Central The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated
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