Antagonistic roles in fetal development and adult physiology for the oppositely imprinted Grb10 and Dlk1genesReportar como inadecuado

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BMC Biology

, 12:771

First Online: 31 December 2014Received: 15 September 2014Accepted: 07 November 2014DOI: 10.1186-s12915-014-0099-8

Cite this article as: Madon-Simon, M., Cowley, M., Garfield, A.S. et al. BMC Biol 2014 12: 771. doi:10.1186-s12915-014-0099-8


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.

KeywordsAdiposity Body proportions Genomic imprinting Glucose-regulated metabolism Growth Mouse genetics AbbreviationsANOVAanalysis of variance

BMCbone mineral content

BMDbone mineral density

CDKN1Ccyclin-dependent kinase inhibitor 1C

CI-MPRcation-independent mannose 6-phosphate receptor

CNScentral nervous system

Dlk1Delta-like 1

DXAdual energy X-ray absorptiometry

E11.5 to E175: mouse embryonic days 11.5 to 17.5

EDTAethylenediaminetetraacetic acid

FACSfluorescence activated cell sorting

G1-phasecell cycle growth phase 1

G2-phasecell cycle growth phase 2

Grb10growth factor receptor-bound protein 10

H and Ehaematoxylin and eosin

IGFinsulin-like growth factor

Igf2insulin-like growth factor 2

Igf2rinsulin-like growth factor type 2 receptor

Insrinsulin recptor

m-TORmammalian target of rapamycin

OCToptimal cutting temperature

PBSphosphate-buffered saline


PMEFprimary mouse embryonic fibroblast

pref-1preadipocyte factor-1

SEMstandard error of the mean

S-phasecell cycle DNA synthesis phase

WATwhite adipose tissue


Electronic supplementary materialThe online version of this article doi:10.1186-s12915-014-0099-8 contains supplementary material, which is available to authorized users.

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Autor: Marta Madon-Simon - Michael Cowley - Alastair S Garfield - Kim Moorwood - Steven R Bauer - Andrew Ward


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