Disease relevance of Dlk1

• Pref-1 transgenic mice with a substantial, but not complete, loss of adipose tissue exhibited hypertriglyceridemia, impaired glucose tolerance, and decreased insulin sensitivity [1].
• Pref-1-null mice display growth retardation, obesity, blepharophimosis, skeletal malformation, and increased serum lipid metabolites [2].
• In nude mice, UM-SCP-1 produces rapidly growing tumors with distinct histological features of squamous cell carcinoma [3].

High impact information on Dlk1

• Here we report the cloning of new complementary DNAs that encode the 3T3 preadipocyte factor (termed AEBP1) and demonstrate that AEBP1 expression is abolished during adipocyte differentiation [4].
• Furthermore, we show that Dlk1 is tightly linked to the maternally expressed Gtl2 gene [5].
• In preadipocytes Foxa-2 inhibits adipocyte differentiation by activating transcription of the Pref-1 gene [6].
• These findings demonstrate the inhibition of adipogenesis by Pref-1 in vivo and the resulting impairment of adipocyte function that leads to the development of metabolic abnormalities [1].
• Mice expressing the Pref-1/hFc transgene exclusively in liver under the control of the albumin promoter also showed a decrease in adipose mass and adipocyte marker expression, suggesting an endocrine mode of action of Pref-1 [1].

Biological context of Dlk1

• Dlk1 and Gtl2 are reciprocally imprinted genes located 80 kb apart on mouse chromosome 12 [7].
• Here we describe a detailed methylation analysis of the Dlk1-Gtl2 domain on both parental alleles in the mouse [7].
• Preadipocyte factor 1 (Pref-1/Dlk1) inhibits in vitro adipocyte differentiation and has been recently reported to be a paternally expressed imprinted gene at human chromosome 14q32 [2].
• DNA methylation imprints on the IG-DMR of the Dlk1-Gtl2 domain in mouse male germline [8].
• Mouse genomes show a large cluster of imprinted genes at the Dlk1-Gtl2 domain in the distal region of chromosome 12 [8].

Anatomical context of Dlk1

• Overexpression of Dlk1 prevents adipogenesis of 3T3-L1 cells [9].
• Dlk1-deficient mice are obese; however, adipose tissue still develops in Fc-dlk1 transgenic mice, suggesting that Dlk1 is not a strict inhibitor of adipogenesis [9].
• Expression of Cyp11B2 and preadipocyte factor 1 is lowered in the glands of Wnt-4 mutant animals, resulting in significantly reduced aldosterone production in the newborn mutants, suggesting that Wnt-4 may be needed for proper formation of the zona glomerulosa [10].
• In order to isolate and to characterize hepatoblasts, we searched for cell surface antigens expressed in mouse fetal hepatic cells by the signal sequence trap method and found that Dlk, also known as Pref-1, was strongly expressed in fetal liver [11].
• In addition, numerous microvilli were observed by electronmicroscopic analysis in most of those cultured cells, also indicating differentiation of Dlk+ cells under this condition [11].

Associations of Dlk1 with chemical compounds

• Inhibition of adipogenesis and development of glucose intolerance by soluble preadipocyte factor-1 (Pref-1) [1].
• Unexpectedly, we found that forced expression of the soluble form, FA1, or full-length Pref-1 did not inhibit adipocyte differentiation of 3T3-L1 cells when differentiation was induced by standard treatment with methylisobutylxanthine, dexamethasone, and high concentrations of insulin [12].
• Gene-expression XY-scatterplots using Clontech mouse 1.2 Atlas mouse cDNA expression arrays analyzing total uterine RNA showed nerve growth factor-alpha, preadipocyte factor-1, and insulin-like growth factor-2 were key genes differentially modified by tamoxifen or toremifene treatment, relative to the controls [13].
• Northern blot analysis was used to determine messenger RNA (mRNA) steady state expression of Pref-1 and two differentiation-specific genes, adipsin and glycerol-3-phosphate dehydrogenase [14].
• Judging by Oil Red O staining for lipid accumulation and expression of adipocyte markers, we determined that, unlike the full-length Pref-1A and the constructed large soluble form, the artificial membrane form of Pref-1 lacking the processing site proximal to the membrane was not effective in inhibiting adipogenesis [15].

Regulatory relationships of Dlk1

• TNF alpha-mediated inhibition and reversal of adipocyte differentiation is accompanied by suppressed expression of PPARgamma without effects on Pref-1 expression [16].
• These results indicate that Pref-1 expressed by TE cells and HES-1 expressed by thymocytes are critically involved in supporting thymocyte cellularity [17].

Other interactions of Dlk1

• The imprinted Dlk1-Dio3 region on mouse chromosome 12 contains six imprinted genes and a number of maternally expressed snoRNAs and miRNAs [18].
• We show that the two genes located immediately proximal to Dlk1, the Yy1 and Wars genes, are expressed in a biallelic manner [19].
• Imprinting of Igf2r, Kcnq1, Gt12, and Dlk1 varied among individuals [20].
• Dlk was expressed exclusively from the paternal allele in both the embryo and placenta, but the CpG-island promoter of Dlk was completely unmethylated on both parental alleles [21].
• Insulin-like growth factor-1/insulin bypasses Pref-1/FA1-mediated inhibition of adipocyte differentiation [12].

Analytical, diagnostic and therapeutic context of Dlk1

• Assignment of dlk (Dlk1) to mouse chromosome band 12E-F1 by in situ hybridization [22].
• In addition, coculture of C3H10T1/2 cells with other cells expressing Dlk1, but not with cells lacking Dlk1 expression, enhances their adipogenic response [9].
• 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 [23].
• By transplantation of Dlk+ cells into the spleen, donor-derived hepatocytes were found in the recipient liver, indicating that Dlk+ cells differentiated into hepatocytes in vivo [11].
• Through RT-PCR and the isolation and analysis of multiple pref-1 cDNA clones, we have identified, in addition to full-length pref-1, five alternately spliced forms with various in-frame deletions of all or a part of the sixth EGF-like repeat, juxta-membrane, and predicted transmembrane domains.(ABSTRACT TRUNCATED AT 250 WORDS)[24]

References