Disease relevance of Gtl2

• RESULTS: A previously existing insertional mutation (Gtl2lacZ), and a targeted deletion in which the Gtl2 upstream region was replaced by a Neo cassette (Gtl2Delta5'Neo), display partial lethality and dwarfism upon paternal inheritance [1].

High impact information on Gtl2

• Furthermore, we show that Dlk1 is tightly linked to the maternally expressed Gtl2 gene [2].
• Additionally, this analysis facilitated identification of a CpG-rich tandem repeat array located approximately 13-15 kb upstream of Gtl2 [3].
• Using conceptuses with maternal or paternal uniparental disomy for chromosome 12 (UPD12), we found that Gtl2 is expressed from the maternal allele and methylated at the 5' end of the silent paternal allele [4].
• Gtl2 encodes multiple alternatively spliced transcripts with no apparent open reading frame [4].
• DNA methylation imprints on the IG-DMR of the Dlk1-Gtl2 domain in mouse male germline [5].

Biological context of Gtl2

• Dlk1 and Gtl2 are reciprocally imprinted genes located 80 kb apart on mouse chromosome 12 [6].
• Here we describe a detailed methylation analysis of the Dlk1-Gtl2 domain on both parental alleles in the mouse [6].
• The aberrant induction of Megs from silent paternal alleles was also observed in association with changes in the DNA methylation level of a differentially methylated region (DMR) located around Meg3/Gtl2 exon 1 [7].
• Gtl2(lacZ) (Gene trap locus 2) mice have a transgene (TG) insertion 2.3 kb upstream from the Meg3/Gtl2 promoter and show about 40% growth retardation when the TG-inserted allele is paternally derived [7].
• Mouse genomes show a large cluster of imprinted genes at the Dlk1-Gtl2 domain in the distal region of chromosome 12 [5].

Anatomical context of Gtl2

• Molecular characterization and expression of maternally expressed gene 3 (Meg3/Gtl2) RNA in the mouse inner ear [8].
• Furthermore, we show that the BAC Gtl2 gene is expressed at levels approaching those of the endogenous gene only in the brain of adult animals, not in other sites of endogenous expression such as the pituitary, adrenal, and skeletal muscle [9].
• Meg3/Gtl2 RNA expression increased in the developing otocyst and localized to the spiral ganglion, stria vascularis, Reissner's membrane, and greater epithelial ridge (GER) in the cochlear duct [8].
• Erasure of methylation marks on Gtl2 appears to occur later in female germ cells to give the unmethylated profile seen in mature MII oocytes [10].
• In early postimplantation embryos, Gtl2 is expressed in the visceral yolk sac and embryonic ectoderm [11].

Other interactions of Gtl2

• RT-PCR experiments support the predicted presence of a maternally expressed intergenic transcript(s) encompassing Gtl2, Rian, and Mirg [12].
• To elucidate the mechanism underlying such a variation, we examined the expression of two genes from the distal Chr 12 imprinted region, the maternally expressed gene 3/gene-trap locus 2 ( Meg3/ Gtl2), and the delta-like homolog 1 ( Dlk1) gene [13].
• High-resolution map and imprinting analysis of the Gtl2-Dnchc1 domain on mouse chromosome 12 [12].
• In addition, we have analyzed the Dio3 gene, located distal to Gtl2 [14].
• We examined methylation of the Rasgrf1 and Gtl2 differentially methylated regions (DMR) to determine whether methylation is erased in male germ cells at e12.5 and when the paternal allele acquires methylation [10].

Analytical, diagnostic and therapeutic context of Gtl2

• Here we present a high-resolution sequence analysis of the 1.1-Mb segment telomeric to Gtl2 in mouse and a homology comparison to the human [12].
• We have used BAC transgenesis in the mouse to begin to delineate the region of DNA required for proper expression and imprinting of the mouse Delta-like1 (Dlk1) and Gene-trap locus2 (Gtl2) imprinted genes [9].
• Nuclear Gtl2 RNA was detected in a temporally and spatially regulated manner, and partially processed Gtl2 transcripts were readily detected in Northern blot hybridizations of polyadenylated RNA, suggesting that primary Gtl2 transcripts are differently processed in various cell types during development [11].
• Real-time PCR analysis demonstrated that Meg3/Gtl2 was highly expressed in the cochlea, brain, and eye [8].
• By using microarray analysis, we identified several transcripts enriched in the inner ear, including the maternally expressed gene 3 (Meg3/Gtl2), an imprinted noncoding RNA [8].

References