Alternative titles; symbols
HGNC Approved Gene Symbol: DLK1
Cytogenetic location: 14q32.2 Genomic coordinates (GRCh38): 14:100,726,892-100,738,224 (from NCBI)
DLK1 is an epidermal growth factor (EGF; 131530) repeat-containing transmembrane protein that is cleaved by TACE (ADAM17; 603639) to generate a biologically active soluble form. By interacting with fibronectin (FN1; 135600), soluble DLK1 activates integrin downstream signaling to activate MEK (see 176872)/ERK (see 601795), upregulate SOX9 (601860), and inhibit adipocyte differentiation (Wang et al., 2010).
In mice, Smas and Sul (1993) cloned a regulator of adipocyte differentiation called preadipocyte factor-1, a novel member of the epidermal growth factor (EGF)-like family of proteins. It was synthesized as a transmembrane protein with 6 tandem EGF-like repeats. In preadipocytes, multiple discrete forms of the protein product of 45 to 60 kD were present, owing in part to N-linked glycosylation. While PREF1 mRNA was abundant in preadipocytes, its expression was completely abolished during differentiation of cultured preadipocytes to adipocytes.
Helman et al. (1987) identified pG2, a human cDNA that is more highly expressed in pheochromocytoma, the adrenal medullary neuroendocrine tumor, than in neuroblastoma, the more immature embryonal tumor of adrenal medulla. In normal tissues, pG2 was highly expressed specifically in the adrenal cortex. Lee et al. (1995) stated that several studies suggested a correlation between the level of pG2 expression and the induction of a neuronal or neuroendocrine phenotype.
Laborda et al. (1993) isolated human and mouse cDNAs encoding a protein that they designated DLK (Delta-like) because of its homology to the Drosophila neurogenic protein Delta, which is involved in neural differentiation. The predicted 383-amino acid human protein shares 86% identity with mouse Dlk. Both human and mouse DLK contain 6 EGF-like repeats, a transmembrane region, and a signal peptide domain. Northern blot analysis revealed that the DLK gene was expressed in tumors with neuroendocrine features, such as neuroblastoma, pheochromocytoma, and a subset of small cell lung carcinoma cell lines; however, its expression in normal tissues was restricted to the adrenal gland and placenta. The authors suggested that DLK may be involved in neuroendocrine differentiation.
Jensen et al. (1994) isolated a circulating form of fetal antigen-1 (FA1) from human amniotic fluid during the second trimester of pregnancy. They reported that FA1 is identical to pG2 and DLK and attributed sequence differences between FA1 and pG2 to errors in DNA sequencing. Sequence analysis revealed that the N-terminal 23 amino acids of FA1 define a signal peptide, suggesting that FA1 is synthesized as a membrane-bound precursor that is subsequently cleaved to generate the circulating form. Using immunofluorescence, Jensen et al. (1994) found that FA1 colocalizes with insulin to the insulin secretory granules of the beta cells within the islets of Langerhans. Immunohistochemical experiments demonstrated that FA1 was expressed in 10 of 14 lung tumors classified as neuroendocrine tumors, and in the placental villi.
Lee et al. (1995) reported that DLK, pG2, and PREF1 are variant products of the same gene. They noted that C. Smas and H.S. Sul acknowledged in a personal communication that the major point of divergence between mouse Dlk and Pref1 was due to sequence data misinterpretation. Sequence analysis of multiple human DLK cDNAs revealed that there are several variant forms of DLK mRNA.
Mei et al. (2002) stated that the deduced full-length mouse Pref1 protein has an N-terminal signal sequence, followed by an extracellular domain, a transmembrane domain, and a short cytoplasmic tail. The extracellular domain contains 6 EGF-like repeats, a juxtamembrane region, and 2 proteolytic processing sites. Upon cleavage, Pref1 releases either a 50-kD soluble fragment including all 6 EGF-like repeats or a 25-kD fragment including only the 3 N-terminal EGF-like repeats. Splice variants of Pregf1 encode 3 additional isoforms with deletions involving EGF-like repeat-6 and/or the juxtamembrane region.
Dauber et al. (2017) measured Dlk1 expression in the mediobasal hypothalamus (MBH) of juvenile wildtype male mice and in 2 immortalized mouse cell lines, KTaR-1 and KTaV-3, derived from kisspeptin neurons in the arcuate and anteroventral periventricular nuclei, respectively. Dlk1 expression was detected in the mouse MBH and in both cell lines, at significantly higher levels than in HEK293 cells, and expression was significantly higher in the MBH than in the cell lines. The authors stated that these findings further supported a role for DLK1 in regulating pubertal timing, possibly by influencing kisspeptin signaling.
By fluorescence in situ hybridization, Gubina et al. (1999) mapped the DLK1 gene to chromosome 14q32.
By expressing splice variants and artificial constructs of Pref1 in 3T3-L1 cells and by exposing 3T3-L1 cells to conditioned media from transfected COS cells, Mei et al. (2002) showed that only the large soluble form of Pref1 containing all 6 EGF-like domains could inhibit adipocyte differentiation. Membrane-bound forms of Pref1 lacking the membrane proximal proteolytic processing site did not inhibit adipogenesis. The small soluble form of Pref1 that contains only the first 3 EGF-like repeats was similarly inactive in inhibiting adipogenesis.
Using yeast 2-hybrid analysis with an embryonic mouse cDNA library and other protein interaction assays, Wang et al. (2010) showed that the ectodomain and juxtamembrane region of soluble Pref1 interacted with the C terminus of fibronectin, an inhibitor of adipocyte differentiation. Pref1-mediated inhibition of 3T3-L1 cell differentiation was accompanied by Mek/Erk signaling, induction of Sox9, and activation of the integrin downstream signaling molecules Fak (PTK2; 600758) and Rac (RAC1; 602048). Knockdown of fibronectin prevented Pref1-mediated inhibition of differentiation, Mek/Erk activation, and Sox9 induction. Pref1-mediated activation of Mek/Erk was blunted by knockdown of Rac or forced expression of dominant-negative Rac. Wang et al. (2010) concluded that, by interacting with fibronectin, Pref1 activates integrin downstream signaling to activate MEK/ERK and inhibit adipocyte differentiation.
Muller et al. (2014) identified DLK1 as a determinant of motor neuron functional diversification. DLK1, expressed by approximately 30% of motor neurons, is necessary and sufficient to promote a fast biophysical signature in mouse and chick. DLK1 suppresses Notch signaling and activates expression of the potassium ion channel subunit KCNG4 (607603) to modulate delayed-rectifier currents. DLK1 inactivation comprehensively shifts motor neurons toward slow biophysical and transcriptome signatures, while abolishing peak force outputs. Muller et al. (2014) concluded that their findings provided insights into the development of motor neuron functional diversity and its contribution to the execution of movements.
Using data and samples from a prospective cohort of women with first pregnancies from the Pregnancy Outcome Prediction study, Cleaton et al. (2016) studied 45 women who delivered a small for gestational age (SGA) baby and who had a plasma sample obtained around 36 weeks of gestation. SGA infants with high-resistance uterine and/or umbilical artery flow and/or low abdominal circumference growth velocity were defined as having fetal growth retardation (FGR), and infants with none of those features were designated as having 'healthy' SGA. When compared with matched controls, women with 'healthy' SGA infants showed no significant difference in DLK1 levels, whereas women with FGR infants exhibited a highly statistically significant reduction in DLK1 levels relative to controls (p less than 0.0001). Analysis of the FGR-defining parameters revealed very strong associations between DLK1 concentrations and SGA in the presence of either high-resistance umbilical artery flow (p less than 0.0001) or low abdominal circumference growth velocity (p less than 0.007). The associations were confirmed by receiver operating characteristic (ROC) curve analysis using a random sample of the cohort as controls; the strongest association was again for SGA combined with high-resistance umbilical artery flow. Cleaton et al. (2016) concluded that DLK1 measurements might be clinically useful in differentiating healthy SGA infants from those who are pathologically small.
Imprinting of DLK1
Dlk1 and Gtl2 (605636) are reciprocally imprinted genes located 80 kb apart on mouse chromosome 12. There are similarities between this domain and that of the well-characterized Igf2/H19 locus (see 103280) (Wylie et al., 2000). Takada et al. (2002) described a detailed methylation analysis of the Dlk1/Gtl2 domain on both parental alleles in the mouse. Like the Igf2/H19 domain, areas of differential methylation are hypermethylated on the paternal allele and hypomethylated on the maternal allele. Three differentially methylated regions (DMRs), each with different epigenetic characteristics, were identified. One DMR is intergenic, contains tandem repeats, and is the only region that inherits a paternal methylation mark from the germline. An intronic DMR contains a conserved putative CTCF (604167)-binding domain. All 3 DMRs have both unique and common features compared to those identified in the Igf2/H19 domain.
Lin et al. (2003) studied the intergenic germline-derived DMR (IG-DMR), a candidate control element for an imprinted domain on distal mouse chromosome 12. They showed that deletion of the IG-DMR from the maternally inherited chromosome causes bidirectional loss of imprinting of all genes in the cluster. When the deletion is transmitted from the father, imprinting is unaltered. These results proved that the IG-DMR is a control element for all imprinted genes on the maternal chromosome only and indicated that the 2 parental chromosomes control allele-specific gene expression differently.
In mice, Dlk1 is expressed from the paternally inherited chromosome. Ferron et al. (2011) showed that mice that are deficient in Dlk1 have defects in postnatal neurogenesis in the subventricular zone: a developmental continuum that results in depletion of mature neurons in the olfactory bulb. DLK1 is secreted by niche astrocytes, whereas its membrane-bound isoform is present in neural stem cells and is required for the inductive effect of secreted DLK1 on self-renewal. Notably, Ferron et al. (2011) found that there is a requirement for DLK1 to be expressed from both maternally and paternally inherited chromosomes. Selective absence of Dlk1 imprinting in both neural stem cells and niche astrocytes is associated with postnatal acquisition of DNA methylation at the germline-derived imprinting control region. The results emphasized molecular relationships between neural stem cells and the niche astrocyte cells of the microenvironment, identifying a signaling system encoded by a single gene that functions coordinately in both cell types. Ferron et al. (2011) suggested that the modulation of genomic imprinting in a stem cell environment adds a new level of epigenetic regulation to the establishment and maintenance of the niche, raising wider questions about the adaptability, function, and evolution of imprinting in specific developmental contexts.
Martinez et al. (2016) performed pyrosequencing analysis of cDNA from neonatal foreskins carrying SNPs in the exonic sequences of DLK1 and DIO3 (601038), as well as PCR of cDNA from a skin specimen from an adult male with known parental origin of the DIO3 SNP. They found that both DLK1 and DIO3 exhibited a high degree of monoallelic expression from the paternal allele in neonatal foreskin, whereas the preferentially expressed DIO3 allele was inherited from the mother in the adult skin sample.
In 5 females, including 2 sisters, their 2 paternal half-sister cousins, and their paternal grandmother, with central precocious puberty (CPPB; see 176290), from a Brazilian family of African ancestry in which linkage to the genomic region containing the MKRN3 gene (603856) had been excluded, Dauber et al. (2017) identified heterozygosity for an approximately 14-kb deletion on chromosome 14 (chr14:101,180,303-101,194,231) that encompassed the entire first exon of the DLK1 gene, including the translational start site. Sanger sequencing revealed that a 269- segment from intron 3 of DLK1 had been duplicated and inserted between the ends of the genomic deletion. Segregation analysis of the DLK1 rearrangement followed an imprinted pattern, with the 2 unaffected carrier fathers transmitting the rearrangement with complete penetrance to their affected daughters. All 5 affected individuals had undetectable serum DLK1 levels. Analysis of the DLK1 gene in an additional 19 unrelated patients with CPPB, in whom mutation in the MKRN3 gene had been excluded, revealed no mutations or deletions. Dauber et al. (2017) noted that both MKRN3 and DLK1 are paternally expressed imprinted genes, and that common SNPs near both genes have been reported to affect timing of menarche in the general population when paternally inherited.
The clinical phenotypes of maternal and paternal uniparental disomy of chromosome 14 (UPD14) are distinctive and are attributed to dysregulation of imprinted genes. Maternal UPD14, the inheritance of both chromosome homologs from the mother with no contribution from the father, is characterized by prenatal and postnatal growth retardation, hypotonia, joint laxity, motor delay, early onset of puberty, and minor dysmorphic features of the face, hands, and feet (Sutton and Shaffer, 2000). Paternal UPD14 has a more severe presentation, with polyhydramnios, thoracic and abnormal wall defects, growth retardation, severe developmental delay, and characteristic dysmorphism (Sutton and Shaffer, 2000). Temple et al. (2007) presented a patient with clinical features of maternal UPD14, including growth retardation, hypotonia, scoliosis, small hands and feet, and advanced puberty, who had loss of paternal methylation of the IG-DMR with no evidence of maternal UPD14. A methylation mutation at the 14q32 IG-DMR on the paternal allele, with reduced expression of DLK1, was suspected. This case provided support for the hypothesis that the maternal UPD14 phenotype is due to aberrant gene expression within the imprinted domain at 14q32.
Human chromosome 14q32.2 carries a cluster of imprinted genes including paternally expressed genes (PEGs) such as DLK1 and RTL1 (611896) and maternally expressed genes (MEGs) such as MEG3 (605636), RTL1-antisense (RTL1as), and MEG8, together with the intergenic differentially methylated region (IG-DMR) and the MEG3-DMR. Consistent with this, paternal and maternal uniparental disomy for chromosome 14 causes distinct phenotypes. Kagami et al. (2008) studied 8 individuals with the phenotype like that of paternal uniparental disomy for chromosome 14 (upd(14)pat-like) and 3 individuals with a upd(14)mat-like phenotype in the absence of actual uniparental disomy of chromosome 14. The authors identified various deletions and epimutations affecting the imprinted region. The results, together with mouse data, implied that the IG-DMR has an important cis-acting regulatory function on the maternally inherited chromosome and that excessive RTL1 expression and decreased DLK1 and RTL1 expression are relevant to upd(14)pat-like and upd(14)mat-like phenotypes, respectively.
Based on the evidence at the homologous region in sheep, Wermter et al. (2008) analyzed 32 polymorphisms in a 109-kb region encompassing the DLK1 gene in 1,025 French and German trio families composed of both parents and extremely obese offspring and identified a synonymous C-T SNP (rs1802710) in exon 5 of the DLK1 gene that was associated with child and adolescent obesity. Analysis of the allelic transmission pattern was consistent with polar overdominance. When the parental origin of the transmitted alleles was ignored, the transmission disequilibrium test revealed no evidence of linkage or allelic association with obesity; however, stratification based on parental origin showed more frequent transmission of the paternal C allele to obese children, but the relative risk for carriers of the homozygous C/C genotype was not increased compared to the reference genotype. Wermter et al. (2008) stated that this was the first evidence for polar overdominance in humans, but noted that rs1802710 was located at the edge of a linkage disequilibrium block and that the functional relevance of the silent C-T SNP was unclear.
For discussion of a possible association between variation in the DLK1 gene and type 1 diabetes, see 222100.
Perry et al. (2014) performed a metaanalysis using genomewide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, and found robust evidence (p less than 5 x 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with 3 loci (DLK1-WDR25, 618059; MKRN3, 603856-MAGEL2, 605283; and KCNK9, 605874) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Perry et al. (2014) identified 2 independent signals, rs10144321 and rs7141210, on chromosome 14q32, in a region harboring the reciprocally imprinted genes DLK1 and MEG3, which exhibit paternal-specific or maternal-specific expression, respectively. For both signals the paternally inherited alleles were associated with increasing age at menarche (rs10144321, p(pat) = 3.1 x 10(-5); rs7141210, p(pat) = 2.1 x 10(-4)), but the maternally inherited alleles were not.
Cockett et al. (1996) studied inheritance patterns in sheep with and without 'callipyge' muscular hypertrophy and found that the callipygic phenotype was characterized by a nonmendelian inheritance pattern that they designated 'polar overdominance.' Heterozygous individuals having inherited a paternal callipyge mutation express the phenotype, whereas offspring inheriting the putative mutation from both parents did not exhibit muscular hypertrophy, suggesting that 'inactivation' of the mutated maternal allele dominates the 'activation' of the mutated paternal allele.
Freking et al. (2002) analyzed the callipyge locus on ovine chromosome 18, homologous to the DLK1 region on human chromosome 14 where imprinting is known to occur, and identified a single heterozygous base position that segregated with the callipygic phenotype in a pattern consistent with polar overdominance. The change was located in a region of high homology among mouse, sheep, cattle, and humans, but not in any previously identified transcript.
Lee et al. (2003) generated transgenic mice expressing the full ectodomain corresponding to the large cleavage product of Pref1 in adipose tissue only, and found that they had a substantial decrease in total fat pad weight. Adipose tissue from the transgenic mice showed reduced expression of adipocyte markers and adipocyte-secreted factors, whereas the preadipocyte marker Pref1 was increased. Pref1 transgenic mice with a substantial loss of adipose tissue exhibited hypertriglyceridemia, impaired glucose tolerance, and decreased insulin sensitivity. Mice expressing the transgene exclusively in the liver also showed a decrease in adipose mass and adipocyte marker expression, suggesting an endocrine mode of action of Pref1. Lee et al. (2003) concluded that there is inhibition of adipogenesis by Pref1 in vivo and that the resulting impairment of adipocyte function leads to the development of metabolic abnormalities.
Cleaton et al. (2016) analyzed Dlk1-null mice and 'Mat' maternal heterozygous mice (null maternal allele and wildtype paternal allele). Dlk1-null embryos exhibited reduced size, with a reduction in skeletal length and lean mass, from at least embryonic day 18.5. At 12 weeks, virgin null females had increased abdominal white adipose tissue (WAT) and leptin levels, as well as reduced muscle mass, compared to Dlk1-expressing females. In addition, the authors observed that plasma Dlk1 levels increased approximately 5-fold during the first 2 weeks of mouse pregnancy. Serial measurements of maternal plasma Dlk1 levels in crosses of mice where the mother, the conceptus, or both were unable to express Dlk1 revealed that Dlk1 was detected at high levels in maternal plasma only if the conceptus retained the ability to express Dlk1. Further experiments demonstrated that the fetus, not the placenta, is the source of maternal circulating Dlk1. Females lacking Dlk1 during their own development also gained less adipose tissue during pregnancy, suggesting that maternal loss of Dlk1 limits adipose plasticity during pregnancy; conceptus-derived Dlk1 did not modify any of the body composition parameters. Upon fasting, null females without pregnancy-induced Dlk1 production failed to elevate their circulating ketone levels and were relatively hyperglycemic, despite normal insulin levels; they also did not show the increase in hepatic expression of Hmgcs2 (600234), a rate-limiting enzyme in the ketogenesis pathway, that was observed in null mothers with circulating Dlk1. In addition, the null mothers did not experience the same magnitude reduction in total cholesterol and HDL cholesterol as null females with circulating Dlk1. These findings suggested that failure to elevate Dlk1 levels during pregnancy prevents normal maternal metabolic adaptations. Analysis of growth hormone (GH; 139250) levels showed only a 3-fold elevation in pregnancies entirely lacking Dlk1 compared to a 13-fold rise in wildtype mice, without alterations to endocrine regulators of Gh such as estradiol and corticosterone, and with normal pituitary Gh mRNA levels. Cleaton et al. (2016) concluded that pregnancies without a conceptus-derived increase in maternal plasma Dlk1 levels have altered fuel metabolism, which may in part result from impaired Gh release.
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