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Background  The  Dlk1  and  Gtl2  genes define a region of mouse chromosome 12 that is subject to genomic imprinting, the parental allele-specific expression of a gene. Although imprinted genes play important roles in growth and development, the mechanisms by which imprinting is established and maintained are poorly understood. Differentially methylated regions (DMRs), which carry methylation on only one parental allele, are involved in imprinting control at many loci. The  Dlk1 - Gtl2  region contains three known DMRs, the  Dlk1  DMR in the 3' region of  Dlk1 , the intergenic DMR 15 kb upstream of  Gtl2 , and the  Gtl2  DMR at the  Gtl2  promoter. Three mouse models are analyzed here that provide new information about the regulation of  Dlk1 - Gtl2  imprinting.    Results  A previously existing insertional mutation ( Gtl2lacZ ), and a targeted deletion in which the  Gtl2  upstream region was replaced by a  Neo  cassette ( Gtl2Δ5'Neo ), display partial lethality and dwarfism upon paternal inheritance. Molecular characterization shows that both mutations cause loss of imprinting and changes in expression of the  Dlk1 ,  Gtl2  and  Meg8 / Rian  genes.  Dlk1  levels are decreased upon paternal inheritance of either mutation, suggesting  Dlk1  may be causative for the lethality and dwarfism. Loss of imprinting on the paternal chromosome in both  Gtl2lacZ  and  Gtl2Δ5'Neo  mice is accompanied by the loss of paternal-specific  Gtl2  DMR methylation, while maternal loss of imprinting suggests a previously unknown regulatory role for the maternal  Gtl2  DMR. Unexpectedly, when the  Neo  gene is excised,  Gtl2Δ5'  animals are of normal size, imprinting is unchanged and the  Gtl2  DMR is properly methylated. The exogenous DNA sequences integrated upstream of  Gtl2  are therefore responsible for the growth and imprinting effects.    Conclusion  These data provide further evidence for the coregulation of the imprinted  Dlk1  and  Gtl2  genes, and support a role for  Dlk1  as an important neonatal growth factor. The ability of the  Gtl2lacZ  and  Gtl2Δ5'Neo  mutations to cause long-range changes in imprinting and gene expression suggest that regional imprinting regulatory elements may lie in proximity to the integration site.

Loss of imprinting at the Dlk1-Gtl2 locus caused by insertional mutagenesis in the Gtl2 5' region