Gene dosage effects of the imprinted delta-like homologue 1 (dlk1/pref1) in development: implications for the evolution of imprinting.
Genomic imprinting is a normal process that causes genes to be expressed according to parental origin. The selective advantage conferred by imprinting is not understood but is hypothesised to act on dosage-critical genes. Here, we report a unique model in which the consequences of a single, double, and triple dosage of the imprinted Dlk1/Pref1, normally repressed on the maternally inherited chromosome, can be assessed in the growing embryo. BAC-transgenic mice were generated that over-express Dlk1 from endogenous regulators at all sites of embryonic activity. Triple dosage causes lethality associated with major organ abnormalities. Embryos expressing a double dose of Dlk1, recapitulating loss of imprinting, are growth enhanced but fail to thrive in early life, despite the early growth advantage. Thus, any benefit conferred by increased embryonic size is offset by postnatal lethality. We propose a negative correlation between gene dosage and survival that fixes an upper limit on growth promotion by Dlk1, and we hypothesize that trade-off between growth and lethality might have driven imprinting at this locus.
da Rocha
Simao Teixeira
ST
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.
Charalambous
Marika
M
Lin
Shau-Ping
SP
Gutteridge
Isabel
I
Ito
Yoko
Y
Gray
Dionne
D
Dean
Wendy
W
Ferguson-Smith
Anne C
AC
D000818:Animals; D001842:Bone and Bones / Q000196:embryology / Q000378:metabolism; D002135:Calcium-Binding Proteins; D047108:Embryonic Development; D019143:Evolution, Molecular; D005260:Female; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental; D018392:Genomic Imprinting; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000196:embryology / Q000254:growth & development / Q000378:metabolism
D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins