Affinage

DLK1

Protein delta homolog 1 · UniProt P80370

Length
383 aa
Mass
41.3 kDa
Annotated
2026-06-09
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DLK1 (Pref-1/FA1) is a paternally imprinted transmembrane protein bearing six tandem EGF-like repeats that functions as a master negative regulator of mesenchymal precursor differentiation, governing adipose, skeletal, and broader developmental programs (PMID:8500166, PMID:12101250). The membrane-anchored protein is cleaved by TACE/ADAM17 in its juxtamembrane region to release a biologically active ~50 kDa soluble ectodomain, and only the larger alternatively spliced isoforms that retain the cleavage site are processed and active (PMID:9001251, PMID:19541743, PMID:7519443). This soluble form acts in a paracrine and endocrine manner to block adipogenesis in vivo (PMID:12588883). Mechanistically, soluble Pref-1 binds fibronectin through its juxtamembrane domain in an α5-integrin-dependent fashion, activating FAK/Rac and the downstream MEK/ERK cascade required to inhibit adipocyte differentiation, independently of Notch (PMID:20457810, PMID:17210639). This signaling upregulates the transcription factor Sox9, which directly binds and represses the C/EBPβ and C/EBPδ promoters, and Sox9 likewise mediates DLK1's inhibition of chondrocyte maturation and osteoblast differentiation (PMID:19254573). DLK1 marks very early mesenchymal adipose precursors whose Sox9-dependent maintenance (via Meis1) holds them in an undifferentiated proliferative state required for both embryonic and adult adipose development (PMID:25088414, PMID:30355480). Beyond fat, DLK1 reprograms systemic metabolism toward peripheral lipid oxidation and intersects the GH/IGF1 axis, repressing GH transcription via Pit-1 sites (PMID:25349437, PMID:17485162). DLK1 also signals in context-dependent modes distinct from the canonical adipogenic pathway: its intracellular domain mediates inhibition of hematopoietic differentiation (PMID:15806146), and it can activate Notch1 signaling to drive endothelial angiogenesis and lung cancer cell invasion (PMID:29383634, PMID:24621612). Paternally inherited loss-of-function deletions and frameshift mutations in humans cause familial central precocious puberty accompanied by metabolic abnormalities (PMID:28324015, PMID:30462238).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1993 High

    Established DLK1's foundational identity and function: an unknown EGF-repeat transmembrane protein whose constitutive expression revealed it as a brake on adipocyte differentiation that must be downregulated for fat conversion.

    Evidence cDNA cloning and constitutive overexpression in 3T3-L1 preadipocytes with differentiation assays

    PMID:8500166

    Open questions at the time
    • Molecular mechanism of inhibition undefined
    • Soluble vs membrane-bound activity not yet distinguished
  2. 1994 High

    Defined the structural diversity and circulating nature of DLK1, showing alternative splicing generates isoforms differing in the juxtamembrane/transmembrane region and that a soluble glycosylated form (FA1) circulates and co-localizes with insulin in beta-cell granules.

    Evidence Genomic cloning, RT-PCR, promoter reporter assays, and protein purification/sequencing from amniotic fluid with immunohistochemistry

    PMID:7519443 PMID:7925474

    Open questions at the time
    • Functional difference between isoforms not yet tested
    • Significance of beta-cell localization unresolved
  3. 1997 High

    Resolved how membrane DLK1 becomes the active species: juxtamembrane proteolytic cleavage releases a ~50 kDa ectodomain sufficient on its own to block adipogenesis, defining a paracrine mechanism and explaining why only the longest splice isoforms are active.

    Evidence Cell-free cleavage assays, conditioned-medium immunoprecipitation, recombinant ectodomain expression, and antibody-blocking adipogenesis assays

    PMID:9001251

    Open questions at the time
    • Identity of the cleaving protease not yet established
    • Receptor/binding partner for the ectodomain unknown
  4. 1999 High

    Connected hormonal control of adipogenesis to DLK1 by showing glucocorticoid-driven transcriptional repression of pref-1 (via a defined SAD promoter element) is required for adipoconversion.

    Evidence Nuclear run-on, promoter deletion reporters, gel shift/UV cross-linking, and antisense knockdown with dose-response differentiation in 3T3-L1

    PMID:10212243 PMID:9822638

    Open questions at the time
    • Identity of the ~63 kDa SAD-binding factor undefined
    • Link between transcriptional control and protein-level signaling unmapped
  5. 2003 High

    Demonstrated DLK1 acts in vivo, both as a paracrine and endocrine factor: paternally inherited null mice show obesity and developmental defects, while transgenic soluble ectodomain delivered from fat or liver reduces adipose mass systemically.

    Evidence Imprinted knockout mice with parent-of-origin crosses and aP2/albumin promoter-driven Pref-1/hFc transgenic lines with body composition analysis

    PMID:12101250 PMID:12588883

    Open questions at the time
    • Downstream signaling pathway in vivo not defined
    • Tissue targets of circulating ectodomain unidentified
  6. 2005 Medium

    Revealed that DLK1 signaling is context- and isoform-dependent, with the intracellular domain (not the released ectodomain) mediating inhibition of hematopoietic differentiation, expanding beyond the soluble paracrine paradigm.

    Evidence Domain-deletion DLK1 constructs in HL-60 cells with differentiation and proliferation assays

    PMID:15806146

    Open questions at the time
    • Intracellular domain effectors unidentified
    • Single cell-line context
  7. 2007 High

    Identified MEK/ERK as the signaling node through which soluble Pref-1 blocks adipogenesis, establishing a causal kinase pathway between the ectodomain and suppression of PPARγ2.

    Evidence Purified soluble Pref-1 on null MEFs with phospho-ERK blots, MEK inhibitor, and ERK1/2 siRNA

    PMID:17210639

    Open questions at the time
    • Upstream receptor linking ectodomain to MEK/ERK not yet identified
    • How ERK suppresses PPARγ2 not detailed
  8. 2009 High

    Defined the transcriptional output and the activating protease: Pref-1-induced Sox9 directly represses C/EBPβ/δ to block adipogenesis (and broadly inhibit osteo/chondro maturation), while TACE/ADAM17 was identified as the sheddase generating the active 50 kDa form.

    Evidence Sox9 siRNA/overexpression, ChIP on C/EBP promoters, in vivo null/transgenic validation, and TACE inhibitor with isoform comparison

    PMID:19254573 PMID:19541743

    Open questions at the time
    • Mechanism coupling ERK to Sox9 induction unresolved
    • TACE finding from review-cited pharmacology only
  9. 2010 High

    Identified fibronectin/α5-integrin as the receptor system for soluble Pref-1, placing FAK/Rac upstream of ERK and explicitly excluding Notch from the adipogenic-inhibitory pathway.

    Evidence Co-IP of Pref-1 with fibronectin, fibronectin and α5-integrin siRNA, RGD competition, dominant-negative Rac, and FAK/Rac phospho-blots

    PMID:20457810

    Open questions at the time
    • Whether a direct signaling receptor beyond integrin exists unknown
    • Structural basis of juxtamembrane-fibronectin binding undefined
  10. 2011 Medium

    Extended DLK1 signaling to chondrogenesis through a distinct effector arm, showing FA1 suppresses chondrogenic differentiation via PI3K/Akt (not ERK/p38), with fibronectin again as a mediator.

    Evidence Overexpression/conditioned medium/purified FA1 in ATDC5 cells with Akt/ERK/p38 blots and fibronectin siRNA rescue

    PMID:21724852

    Open questions at the time
    • Cell-type basis for ERK- vs Akt-pathway choice unexplained
    • Single lab/cell line
  11. 2012 Medium

    Connected DLK1 to multiple organ systems and upstream regulation: C/EBPδ activates pref-1 in brown fat to control thermogenesis, DLK1 marks hepatic stellate cells and supports liver regeneration via Wnt, and hypothalamic DLK1 localizes to AVP/oxytocin neurons.

    Evidence C/EBPδ siRNA/ChIP and null-mouse brown fat analysis; HSC siRNA and anti-DLK1 antibody post-hepatectomy; hypothalamic fractionation and immunohistochemistry

    PMID:22298767 PMID:22324440 PMID:22563444

    Open questions at the time
    • Signaling mechanism in each tissue incompletely defined
    • Functional role of neuronal DLK1 not directly tested
  12. 2014 High

    Established DLK1 as a regulator of multiple precursor lineages and systemic metabolism: it marks the earliest mesenchymal adipose precursors required for fat development, opposingly regulates myogenesis by isoform, drives muscular hypertrophy (callipyge), activates Notch in lung cancer invasion, and shifts whole-body fuel use toward lipid oxidation.

    Evidence Pref-1-rtTA lineage tracing/ablation, isoform-specific C2C12 assays, callipyge sheep IHC and transgenic mice, lung cancer overexpression with GSI, and endogenous Dlk1 knock-in metabolic phenotyping

    PMID:15498495 PMID:24582655 PMID:24621612 PMID:25088414 PMID:25349437

    Open questions at the time
    • How membrane vs soluble isoform ratios are set per tissue unclear
    • Mechanism of Notch activation in cancer vs Notch-independence in fat unreconciled
  13. 2017 Medium

    Linked DLK1 to human disease, showing paternally inherited DLK1 deletions cause familial central precocious puberty with hypothalamic expression in kisspeptin neurons.

    Evidence Linkage/whole-genome sequencing, segregation, serum DLK1 ELISA, and mouse hypothalamic/kisspeptin expression analysis

    PMID:28324015

    Open questions at the time
    • Molecular mechanism by which DLK1 sets pubertal timing undefined
    • Cell-autonomous role in kisspeptin neurons untested
  14. 2018 High

    Defined the Sox9-Meis1 axis maintaining adipose precursors and showed DLK1's soluble domain promotes angiogenesis via Notch1/Akt/eNOS, consolidating Sox9 as the central precursor-maintenance node and Notch as a context-specific effector.

    Evidence Inducible Sox9 knockout in Pref-1+ cells with Meis1 manipulation; recombinant DLK1 ectodomain on endothelial cells with DAPT, Notch1 siRNA/antibody, and aortic ring/corneal assays

    PMID:29383634 PMID:30355480

    Open questions at the time
    • Switch between integrin and Notch signaling modes mechanistically unexplained
    • Endothelial study single lab
  15. 2019 Medium

    Confirmed and broadened the human disease link by showing DLK1 frameshift loss-of-function causes precocious puberty co-occurring with obesity, glucose intolerance and PCOS, positioning DLK1 at the reproduction-metabolism interface.

    Evidence DNA sequencing, segregation across three families, serum DLK1 ELISA, and metabolic profiling of carriers

    PMID:30462238

    Open questions at the time
    • Causal pathway from DLK1 loss to metabolic disease unmapped
    • Genotype-phenotype correlation limited
  16. 2021 Medium

    Extended DLK1 to neural and oncologic contexts, showing biallelic (imprint-escaping) hippocampal expression supports adult neurogenesis and cognition, and that surface DLK1 is a tractable therapeutic target via antibody-drug conjugate in neuroblastoma.

    Evidence Allele-specific expression and loss-of-function mouse models with behavioral assays; shRNA knockdown and ADC (ADCT-701) xenograft efficacy in neuroblastoma

    PMID:33712542 PMID:39454577

    Open questions at the time
    • Signaling mechanism in neurogenesis undefined
    • DLK1 driver vs marker role in neuroblastoma not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular identity of the signaling receptor that transduces soluble DLK1 to MEK/ERK, and the determinants that switch DLK1 between fibronectin/integrin-dependent, intracellular-domain-dependent, and Notch-dependent modes across tissues, remain unresolved.
  • No direct signaling receptor for the ectodomain identified
  • Rules governing tissue-specific pathway selection unknown
  • Mechanism linking ERK/integrin signaling to Sox9 induction undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0060089 molecular transducer activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005576 extracellular region 3 GO:0005886 plasma membrane 3
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-1430728 Metabolism 2
Partners
FN1ITGA5NOTCH1

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 Pref-1 (DLK1) is synthesized as a transmembrane protein with six tandem EGF-like repeats; constitutive expression in 3T3-L1 preadipocytes blocks down-regulation of Pref-1 and drastically inhibits adipocyte differentiation, establishing it as a negative regulator of adipogenesis. cDNA cloning, constitutive expression/overexpression in 3T3-L1 preadipocytes with differentiation assay Cell High 8500166
1994 The pref-1 gene consists of five exons and four introns spanning ~7.3 kb; at least five alternatively spliced forms are produced with in-frame deletions affecting the sixth EGF-like repeat, juxtamembrane, and transmembrane domains, establishing that alternate splicing generates structural diversity in DLK1 isoforms. Genomic cloning, RT-PCR, primer extension, transient transfection reporter assay Biochemistry High 7519443
1994 FA1 (the circulating soluble form of DLK1) is a single-chain glycoprotein with six EGF-like repeats containing up to ten O- and N-glycosylation sites; it is 99% identical to the protein encoded by human dlk/pG2 and co-localizes with insulin in beta-cell secretory granules of the pancreas. Protein purification from amniotic fluid, amino acid sequencing, glycosylation mapping, immunohistochemistry European journal of biochemistry High 7925474
1997 Membrane-associated Pref-1 is proteolytically cleaved in the juxtamembrane region to generate a ~50 kDa soluble ectodomain and smaller 24–31 kDa products; only the two largest alternatively spliced isoforms (which retain the processing site) undergo cleavage. The purified soluble ectodomain alone is sufficient to block 3T3-L1 adipocyte differentiation, demonstrating a paracrine inhibitory mechanism. Cell-free cleavage assay, immunoprecipitation of conditioned medium, E. coli expression of ectodomain, adipogenesis inhibition assay with antibody blocking Molecular and cellular biology High 9001251
1998 Transcription of the pref-1 gene is repressed by dexamethasone (glucocorticoids) as an early event during adipogenic induction; a specific -183 to -170 bp 'SAD' (suppression in adipocyte differentiation) element mediates this differentiation-dependent suppression, and an ~63 kDa nuclear protein binds this element. Nuclear run-on transcription assay, actinomycin D half-life measurement, stable transfection of 5'-deletion reporter constructs, gel mobility shift assay, UV cross-linking The Journal of biological chemistry High 9822638
1999 Glucocorticoid (dexamethasone)-mediated repression of pref-1 transcription contributes to promotion of adipogenesis; antisense pref-1 expression lowers endogenous pref-1 and enhances adipose conversion at sub-threshold dexamethasone concentrations, demonstrating that pref-1 down-regulation is required for adipoconversion. Stable antisense transfection in 3T3-L1, dose-response differentiation assay, nuclear run-on, actinomycin D chase The Journal of biological chemistry High 10212243
2002 Pref-1/Dlk1 knockout mice display growth retardation, obesity, blepharophimosis, skeletal malformation, and increased serum lipids; the phenotype is present only in heterozygotes with a paternally inherited null allele, confirming that Pref-1 is a paternally expressed imprinted gene required for normal development and adipose tissue homeostasis. Gene-targeted knockout mouse generation, heterozygous parental cross analysis, body composition measurement, lipid metabolite assay Molecular and cellular biology High 12101250
2003 Transgenic mice expressing the large soluble Pref-1 ectodomain (fused to human IgG Fc) in adipose tissue show substantial reduction in fat pad weight and decreased adipocyte marker expression; liver-specific expression also reduces adipose mass, demonstrating an endocrine (circulating) mode of action for soluble Pref-1 in inhibiting adipogenesis in vivo. Transgenic mouse generation with aP2 and albumin promoter-driven Pref-1/hFc, fat pad weighing, adipocyte gene expression, serum metabolite analysis The Journal of clinical investigation High 12588883
2004 Overexpression of DLK1/Pref-1 in human marrow stromal (mesenchymal stem) cells inhibits both adipocyte and osteoblast differentiation without affecting proliferation, maintaining cells in a bipotential undifferentiated state; late-stage differentiation markers are suppressed while lineage commitment markers are unaffected. Retroviral stable transduction of hMSC-TERT, cytochemical staining, FACS, real-time PCR, ex vivo calvaria organ culture bone formation assay Journal of bone and mineral research Medium 15068508
2004 Ectopic DLK1 protein expression in skeletal muscle of callipyge sheep (padumnal heterozygotes, +(MAT)/CLPG(PAT)) is perfectly correlated with muscular hypertrophy; transgenic mice expressing DLK1 in skeletal muscle develop generalized muscular hypertrophy, establishing DLK1 protein as the causal agent of the callipyge phenotype. Immunohistochemistry of sheep skeletal muscle, transgenic mouse generation with skeletal muscle-specific DLK1 expression, muscle mass quantification Current biology High 15498495
2005 DLK1 expression in hematopoietic HL-60 cells inhibits differentiation and proliferation; this inhibitory effect requires the intracellular domain of DLK1, not proteolytic release of the extracellular domain, identifying a novel intracellular domain-dependent mechanism distinct from the soluble ectodomain mechanism operative in preadipocytes. Stable transfection of HL-60 cells with full-length and domain-deletion DLK1 constructs, differentiation assay, proliferation assay Oncogene Medium 15806146
2006 DLK1 potentiates adipogenesis in mesenchymal C3H10T1/2 cells (in contrast to its inhibitory effect in preadipocytes); this potentiating effect requires the extracellular EGF-like domain and Notch1 expression, and is associated with altered ERK1/2 activation, demonstrating context-dependent and Notch1-dependent DLK1 action. Overexpression of full-length DLK1, EGF domain only, and intracellular domain constructs in C3H10T1/2; coculture assay; Notch1 siRNA knockdown; ERK1/2 phosphorylation western blot; adipogenesis quantification Journal of molecular biology Medium 17320900
2007 Soluble Pref-1 activates the MEK/ERK pathway in a time- and dose-dependent manner; ERK phosphorylation by Pref-1 is required for inhibition of adipogenesis, as MEK inhibitor PD98059 or ERK1/2 siRNA knockdown abolishes Pref-1's inhibitory effect on adipocyte differentiation (primarily by preventing PPARγ2 induction). Purified soluble Pref-1 treatment of Pref-1-null MEF, phospho-ERK western blot, MEK inhibitor (PD98059) treatment, ERK1/2 siRNA knockdown, lipid accumulation and adipocyte marker expression assay Molecular and cellular biology High 17210639
2007 Circulating FA1 (soluble DLK1) reduces total body weight, fat mass, and bone mass in mice in a dose-dependent manner when overexpressed via hydrodynamic gene transfer; serum FA1 levels are regulated by growth hormone (GH increases FA1 clearance; hypophysectomy increases FA1 ~450%; GH treatment reduces it ~40%), identifying GH as a modulator of circulating DLK1. Hydrodynamic gene transfer in mice, ELISA for FA1, DEXA body composition, bone histomorphometry, GH manipulation (hydrodynamic GH transfer, hypophysectomy) Endocrinology Medium 17446189
2007 DLK1 represses growth hormone (GH) promoter activity in pituitary GH3 cells; this repression requires Pit-1 binding sites in the GH promoter and is independent of DLK1's EGF-like repeats and MAP kinase-modulating activity, identifying GH as a DLK1-regulated target gene via a Pit-1-dependent transcriptional mechanism. Stable DLK1 expression in GH3 cells, GH mRNA/protein/secretion assay, GH promoter-luciferase reporter cotransfection, deletion/mutation analysis of promoter, Pit-1 cotransfection, domain deletion analysis of DLK1 Molecular and cellular endocrinology Medium 17485162
2009 Pref-1 inhibits adipocyte differentiation by upregulating Sox9 expression; Sox9 directly binds the C/EBPβ and C/EBPδ promoters to suppress their activity. Sox9 downregulation is required for adipocyte differentiation to proceed. Furthermore, by inducing Sox9, Pref-1 promotes chondrogenic induction but prevents chondrocyte maturation and osteoblast differentiation. Sox9 siRNA knockdown, Sox9 overexpression, chromatin immunoprecipitation (ChIP) of Sox9 on C/EBP promoters, Pref-1 null and transgenic mice in vivo validation, adipocyte/chondrocyte/osteoblast differentiation assays Cell metabolism High 19254573
2009 Pref-1 is cleaved by TACE (ADAM17/TNF-α-converting enzyme) to generate the biologically active 50 kDa soluble form; only this large soluble form (not the small soluble or transmembrane forms) is biologically active to inhibit adipogenesis. TACE inhibitor treatment, isoform-specific overexpression, adipogenesis assay Molecular endocrinology Medium 19541743
2010 Pref-1 directly interacts with fibronectin via its juxtamembrane domain; this interaction requires fibronectin binding to α5-integrin. Fibronectin is required for Pref-1-mediated ERK/MAPK activation, Sox9 upregulation, and inhibition of adipocyte differentiation. Pref-1 activates integrin downstream signaling molecules FAK and Rac, and ERK activation by Pref-1 is blocked by Rac knockdown or dominant-negative Rac. Pref-1 does not interact with or require Notch for its adipogenic inhibitory function. Co-immunoprecipitation of Pref-1 and fibronectin, fibronectin siRNA knockdown, RGD peptide competition, α5-integrin siRNA knockdown, dominant-negative Rac expression, FAK/Rac phosphorylation western blot, adipogenesis assay Molecular and cellular biology High 20457810
2011 DLK1/FA1 inhibits chondrogenic differentiation of ATDC5 cells in a dose-dependent manner at all stages (proliferation, differentiation, maturation, hypertrophic conversion); this inhibition is mediated through suppression of the PI3K/Akt pathway (not ERK1/2 or p38 MAPK), and fibronectin siRNA rescue of Akt inhibition implicates fibronectin as a mediator of DLK1/FA1-Akt signaling in chondrogenic cells. Stable overexpression and conditioned medium treatment in ATDC5 cells, purified FA1 protein addition, Akt/ERK/p38 western blot, fibronectin siRNA knockdown, cartilage nodule formation assay, collagen type II/X and aggrecan gene expression The Journal of biological chemistry Medium 21724852
2012 DLK1 is expressed selectively in hepatic stellate cells (HSCs) in adult liver; DLK1 knockdown in activated HSCs causes suppression of necdin and Wnt, epigenetic derepression of PPARγ, and morphologic/functional reversal to quiescent cells. Anti-DLK1 antibody administration after partial hepatectomy reduces early hepatocyte proliferation and liver growth, with decreased Wnt10b, β-catenin, cyclins, CDKs, p-ERK1/2, and p-AKT. DLK1 siRNA knockdown in HSCs, anti-DLK1 antibody tail vein injection post-partial hepatectomy, HSC/hepatocyte co-culture, western blot for Wnt/β-catenin/cyclin/CDK/ERK/AKT pathway components The Journal of biological chemistry Medium 22298767
2012 C/EBPδ activates Pref-1 gene transcription in brown adipocytes through binding to the proximal Pref-1 promoter region; C/EBPδ siRNA knockdown reduces Pref-1 expression, and Pref-1 controls the thermogenic gene expression program (UCP1, PGC-1α) in brown adipose tissue. C/EBPδ siRNA knockdown, promoter-reporter assay, ChIP for C/EBPδ binding, Pref-1 mRNA measurement, Pref-1-null mouse brown adipose tissue analysis The Biochemical journal Medium 22324440
2014 Pref-1-marked cells are very early mesenchymal adipose precursors, prior to Zfp423 or PPARγ expression, and Pref-1+ cells are of mesenchymal (not endothelial or pericytal) origin. Ablation of Pref-1-marked cells prevents both embryonic white adipose tissue development and adult adipose expansion upon high-fat feeding, demonstrating that Pref-1+ cells are required for adipogenesis. Pref-1 promoter-rtTA transgenic mice with inducible fluorescent labeling and diphtheria toxin-mediated cell ablation, lineage tracing, embryonic and adult adipose tissue analysis, high-fat diet challenge Cell reports High 25088414
2014 DLK1 overexpression in lung cancer cells promotes invasion through upregulation of MMP9 expression; this MMP9 upregulation depends on Notch signaling, as it is blocked by γ-secretase inhibitor (GSI) treatment, and DLK1 activates Notch signaling (NOTCH1/HES1/NICD nuclear translocation) in lung cancer cells. DLK1 overexpression and knockdown in lung cancer cell lines, transwell invasion assay, western blot and gelatin zymography for MMP9, NOTCH1/HES1 expression and NICD nuclear translocation assay, GSI treatment PloS one Medium 24621612
2014 DLK1 overexpression causes improved glucose tolerance, reduced fat stores, pituitary IGF1 resistance, defective GH feedback regulation, increased circulatory GH, and a switch in whole-body fuel metabolism toward peripheral lipid oxidation and reduced hepatic steatosis, identifying DLK1's physiological function as shifting metabolic mode away from lipid storage. Knock-in mouse overexpressing Dlk1 from endogenous control elements, glucose tolerance test, body composition, hepatic lipid measurement, GH/IGF1 axis analysis, metabolic cage studies Proceedings of the National Academy of Sciences of the United States of America High 25349437
2017 A paternally inherited genomic deletion of DLK1 (including the 5' UTR, first exon, and translational start site) causes familial central precocious puberty (CPP) with undetectable serum DLK1 levels; DLK1 is expressed in mouse hypothalamus and kisspeptin neuron-derived cell lines, implicating DLK1 as a regulator of pubertal timing through the hypothalamic-pituitary-gonadal axis. Linkage analysis, whole-genome sequencing, segregation analysis, ELISA for serum DLK1, in situ hybridization and qRT-PCR in mouse hypothalamus and kisspeptin cell lines The Journal of clinical endocrinology and metabolism Medium 28324015
2018 Soluble DLK1 (extracellular domain) stimulates angiogenesis by activating Notch1/Akt/eNOS/Hes-1 signaling in endothelial cells; pharmacological Notch blockade (DAPT) or Notch1 knockdown/antibody neutralization reverses DLK1-induced endothelial migration and HES-1 activation. Recombinant DLK1 extracellular domain protein treatment of endothelial cells, aortic ring sprouting assay, corneal neovascularization assay, luciferase Hes-1 reporter, DAPT treatment, Notch1 siRNA and neutralizing antibody, Akt/eNOS western blot Angiogenesis Medium 29383634
2018 Sox9 inactivation in Pref-1+ early adipose precursors is required for their transition to PDGFRα+ cells that express early adipogenic markers; Sox9 maintains Pref-1+ cells in a proliferative precursor state by activating Meis1, which prevents adipogenic differentiation. Pref-1+ cells precede PDGFRα+ cells in the adipogenic pathway. Pref-1 promoter-rtTA inducible Sox9 knockout mice, fluorescent labeling and cell sorting, adipogenic marker gene expression, Meis1 overexpression and knockdown Cell reports High 30355480
2019 Loss-of-function frameshift mutations of DLK1 (p.Gly199Alafs*11, p.Val271Cysfs*14, p.Pro160Leufs*50) cause familial central precocious puberty with undetectable serum DLK1; affected women show high prevalence of metabolic abnormalities (obesity, glucose intolerance, hyperlipidemia, polycystic ovary syndrome), demonstrating DLK1 as a link between reproduction and metabolism. DNA sequencing, segregation analysis, serum DLK1 ELISA, metabolic profiling of mutation carriers vs. controls The Journal of clinical endocrinology and metabolism Medium 30462238
2021 Short hairpin RNA-mediated silencing of DLK1 in neuroblastoma cells increases cellular differentiation; high DLK1 expression correlates with a super-enhancer and robust cell surface protein expression, and DLK1-targeting antibody-drug conjugate (ADCT-701) shows potent cytotoxicity in DLK1-expressing neuroblastoma xenograft models. shRNA DLK1 knockdown in neuroblastoma cells, differentiation assay, immunofluorescence/flow cytometry/IHC for cell surface DLK1, in vivo xenograft ADC treatment Cancer cell Medium 39454577
2014 Membrane-bound Dlk1 promotes myogenic differentiation (hypertrophic phenotype, higher fusion rate) in C2C12 cells, whereas soluble Dlk1 inhibits myotube formation, demonstrating that the two isoforms have opposing effects on myogenesis. Stable expression of membrane-bound vs. soluble Dlk1 isoforms in C2C12 cells, myotube formation assay, fusion rate quantification, myogenic gene expression FEBS letters Medium 24582655
2021 In the subgranular zone (SGZ) of the hippocampus, Dlk1 is expressed biallelically (loss of canonical imprinting); both parental alleles are required for normal adult hippocampal neurogenesis and stem cell behavior. Reduction in Dlk1 dosage (maternal, paternal, or biallelic mutations) triggers specific cognitive abnormalities affecting discrimination of environmental stimuli. Dlk1 mutant mouse allele-specific expression analysis in SGZ, adult neurogenesis quantification, behavioral battery (spatial learning, anxiety, discrimination tasks) Proceedings of the National Academy of Sciences of the United States of America Medium 33712542
2012 In the hypothalamus, DLK1 is expressed predominantly as a soluble cleaved form; DLK1 protein is localized to somata and dendrites of arginine-vasopressin neurons in PVN, SCN, and SON and of oxytocin neurons in PVN and SON, suggesting a role in post-natal development of these neuroendocrine systems. Western blot of hypothalamus protein extracts, immunohistochemistry with co-labeling for AVP and oxytocin neuronal markers PloS one Medium 22563444

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 Pref-1, a protein containing EGF-like repeats, inhibits adipocyte differentiation. Cell 578 8500166
2002 Mice lacking paternally expressed Pref-1/Dlk1 display growth retardation and accelerated adiposity. Molecular and cellular biology 382 12101250
2008 Genomic imprinting at the mammalian Dlk1-Dio3 domain. Trends in genetics : TIG 339 18471925
2009 The DLK-1 kinase promotes mRNA stability and local translation in C. elegans synapses and axon regeneration. Cell 294 19737525
1998 Delta-1 activation of notch-1 signaling results in HES-1 transactivation. Molecular and cellular biology 283 9819428
2003 Isolation of hepatoblasts based on the expression of Dlk/Pref-1. Journal of cell science 279 12665558
2012 The microRNAs within the DLK1-DIO3 genomic region: involvement in disease pathogenesis. Cellular and molecular life sciences : CMLS 227 22825660
2003 Inhibition of adipogenesis and development of glucose intolerance by soluble preadipocyte factor-1 (Pref-1). The Journal of clinical investigation 223 12588883
2004 Regulation of human skeletal stem cells differentiation by Dlk1/Pref-1. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 197 15068508
2009 Minireview: Pref-1: role in adipogenesis and mesenchymal cell fate. Molecular endocrinology (Baltimore, Md.) 188 19541743
2009 Pref-1 regulates mesenchymal cell commitment and differentiation through Sox9. Cell metabolism 185 19254573
1997 Cleavage of membrane-associated pref-1 generates a soluble inhibitor of adipocyte differentiation. Molecular and cellular biology 170 9001251
1997 TNF alpha-mediated inhibition and reversal of adipocyte differentiation is accompanied by suppressed expression of PPARgamma without effects on Pref-1 expression. Endocrinology 167 9202217
2000 A role for pref-1 and HES-1 in thymocyte development. Journal of immunology (Baltimore, Md. : 1950) 164 10605019
2006 Pref-1, a preadipocyte secreted factor that inhibits adipogenesis. The Journal of nutrition 156 17116701
2017 Paternally Inherited DLK1 Deletion Associated With Familial Central Precocious Puberty. The Journal of clinical endocrinology and metabolism 147 28324015
2012 Possible roles of DLK1 in the Notch pathway during development and disease. Biochimica et biophysica acta 145 22353464
2000 Does fetal antigen 1 (FA1) identify cells with regenerative, endocrine and neuroendocrine potentials? A study of FA1 in embryonic, fetal, and placental tissue and in maternal circulation. Differentiation; research in biological diversity 139 10997592
1994 Protein structure of fetal antigen 1 (FA1). A novel circulating human epidermal-growth-factor-like protein expressed in neuroendocrine tumors and its relation to the gene products of dlk and pG2. European journal of biochemistry 138 7925474
2019 Astragalus polysaccharides (PG2) Enhances the M1 Polarization of Macrophages, Functional Maturation of Dendritic Cells, and T Cell-Mediated Anticancer Immune Responses in Patients with Lung Cancer. Nutrients 136 31547048
2013 Pref-1, a gatekeeper of adipogenesis. Frontiers in endocrinology 136 23840193
2007 Pref-1 (preadipocyte factor 1) activates the MEK/extracellular signal-regulated kinase pathway to inhibit adipocyte differentiation. Molecular and cellular biology 135 17210639
1999 Autonomous and non-autonomous regulation of mammalian neurite development by Notch1 and Delta1. Current biology : CB 132 10607588
1999 Transcriptional repression of pref-1 by glucocorticoids promotes 3T3-L1 adipocyte differentiation. The Journal of biological chemistry 131 10212243
2010 Pref-1 interacts with fibronectin to inhibit adipocyte differentiation. Molecular and cellular biology 127 20457810
2006 The EGF-like protein dlk1 inhibits notch signaling and potentiates adipogenesis of mesenchymal cells. Journal of molecular biology 113 17320900
2014 Pref-1 marks very early mesenchymal precursors required for adipose tissue development and expansion. Cell reports 107 25088414
2004 Ectopic expression of DLK1 protein in skeletal muscle of padumnal heterozygotes causes the callipyge phenotype. Current biology : CB 104 15498495
1994 Structural characterization and alternate splicing of the gene encoding the preadipocyte EGF-like protein pref-1. Biochemistry 104 7519443
2006 Dlk1 expression marks developing endothelium and sites of branching morphogenesis in the mouse embryo and placenta. Developmental dynamics : an official publication of the American Association of Anatomists 95 16456855
1999 Delta1 expression during avian hair cell regeneration. Development (Cambridge, England) 95 9927597
2008 Human Delta1-pyrroline-5-carboxylate synthase: function and regulation. Amino acids 88 18401542
2008 Suppression of Th2 cell development by Notch ligands Delta1 and Delta4. Journal of immunology (Baltimore, Md. : 1950) 87 18209061
2019 DLK1 Is a Novel Link Between Reproduction and Metabolism. The Journal of clinical endocrinology and metabolism 86 30462238
2012 Regulation of DLK-1 kinase activity by calcium-mediated dissociation from an inhibitory isoform. Neuron 84 23141066
2005 Dlk1 in normal and abnormal hematopoiesis. Leukemia 80 15959531
2006 DLK1: increased expression in gliomas and associated with oncogenic activities. Oncogene 72 16288219
2005 Expression of DLK1 in hematopoietic cells results in inhibition of differentiation and proliferation. Oncogene 71 15806146
2000 Function of pref-1 as an inhibitor of adipocyte differentiation. International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity 71 11126233
2012 Hepatic stellate cell-derived delta-like homolog 1 (DLK1) protein in liver regeneration. The Journal of biological chemistry 70 22298767
2008 Dlk1 influences differentiation and function of B lymphocytes. Stem cells and development 68 18513163
2004 Expression of Dlk/Pref-1 defines a subpopulation in the oval cell compartment of rat liver. Gene expression patterns : GEP 68 15567716
1999 Expression of the mouse Delta1 gene during organogenesis and fetal development. Mechanisms of development 66 10473134
2002 Expression of Notch ligands, Jagged1, 2 and Delta1 in antigen presenting cells in mice. Immunology letters 64 11841846
1998 Transcriptional control of the pref-1 gene in 3T3-L1 adipocyte differentiation. Sequence requirement for differentiation-dependent suppression. The Journal of biological chemistry 64 9822638
2014 DLK1 promotes lung cancer cell invasion through upregulation of MMP9 expression depending on Notch signaling. PloS one 63 24621612
2014 ICR noncoding RNA expression controls imprinting and DNA replication at the Dlk1-Dio3 domain. Developmental cell 62 25263792
2007 Dlk1/FA1 is a novel endocrine regulator of bone and fat mass and its serum level is modulated by growth hormone. Endocrinology 60 17446189
2019 The imprinted gene Delta like non-canonical Notch ligand 1 (Dlk1) is conserved in mammals, and serves a growth modulatory role during tissue development and regeneration through Notch dependent and independent mechanisms. Cytokine & growth factor reviews 59 30930082
1995 dlk, pG2 and Pref-1 mRNAs encode similar proteins belonging to the EGF-like superfamily. Identification of polymorphic variants of this RNA. Biochimica et biophysica acta 59 7711066
1996 FA1 immunoreactivity in endocrine tumours and during development of the human fetal pancreas; negative correlation with glucagon expression. Histochemistry and cell biology 58 8985741
2016 Regulation of the imprinted Dlk1-Dio3 locus by allele-specific enhancer activity. Genes & development 56 26728555
2014 DLK1/PREF1 regulates nutrient metabolism and protects from steatosis. Proceedings of the National Academy of Sciences of the United States of America 55 25349437
2001 Neurons in the monoaminergic nuclei of the rat and human central nervous system express FA1/dlk. Neuroreport 53 11742219
1996 Mouse fetal antigen 1 (mFA1), the circulating gene product of mdlk, pref-1 and SCP-1: isolation, characterization and biology. Journal of reproduction and fertility 53 8882295
2020 Heterogeneity of Satellite Cells Implicates DELTA1/NOTCH2 Signaling in Self-Renewal. Cell reports 52 32023464
2021 The role of delta-like non-canonical Notch ligand 1 (DLK1) in cancer. Endocrine-related cancer 51 34627131
2011 Delta-like 1/fetal antigen-1 (Dlk1/FA1) is a novel regulator of chondrogenic cell differentiation via inhibition of the Akt kinase-dependent pathway. The Journal of biological chemistry 51 21724852
1997 Molecular mechanisms of adipocyte differentiation and inhibitory action of pref-1. Critical reviews in eukaryotic gene expression 50 9607168
2018 Postsynaptic δ1 glutamate receptor assembles and maintains hippocampal synapses via Cbln2 and neurexin. Proceedings of the National Academy of Sciences of the United States of America 49 29784783
2003 Insulin-like growth factor-1/insulin bypasses Pref-1/FA1-mediated inhibition of adipocyte differentiation. The Journal of biological chemistry 49 12651852
2018 Dlk1-Dio3 locus-derived lncRNAs perpetuate postmitotic motor neuron cell fate and subtype identity. eLife 48 30311912
2002 Pref-1 and ADSF/resistin: two secreted factors inhibiting adipose tissue development. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 48 12660879
2018 Soluble delta-like 1 homolog (DLK1) stimulates angiogenesis through Notch1/Akt/eNOS signaling in endothelial cells. Angiogenesis 47 29383634
2002 Expression of preadipocyte factor-1(Pref-1), a delta-like protein, in healing mouse ears. Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society 47 12191003
2012 DLK1 is a somato-dendritic protein expressed in hypothalamic arginine-vasopressin and oxytocin neurons. PloS one 45 22563444
2020 DLK1, Notch Signaling and the Timing of Puberty. Seminars in reproductive medicine 44 31972862
2007 Anti-adipogenic action of pitavastatin occurs through the coordinate regulation of PPARgamma and Pref-1 expression. British journal of pharmacology 44 17549051
1998 Expression patterns of Notch1, Serrate1, Serrate2 and Delta1 in tissues of the developing chick limb. Mechanisms of development 42 9831652
2008 Human serum levels of fetal antigen 1 (FA1/Dlk1) increase with obesity, are negatively associated with insulin sensitivity and modulate inflammation in vitro. International journal of obesity (2005) 41 18392037
2021 Emerging Roles of DLK1 in the Stem Cell Niche and Cancer Stemness. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 39 34606325
2020 The Role of Pref-1 during Adipogenic Differentiation: An Overview of Suggested Mechanisms. International journal of molecular sciences 38 32526833
2014 RPM-1 uses both ubiquitin ligase and phosphatase-based mechanisms to regulate DLK-1 during neuronal development. PLoS genetics 37 24810406
1993 Fetal antigen 1 (FA1) in the human pancreas: cell type expression, topological and quantitative variations during development. Anatomy and embryology 37 8512086
2018 Sox9-Meis1 Inactivation Is Required for Adipogenesis, Advancing Pref-1+ to PDGFRα+ Cells. Cell reports 36 30355480
2007 Regulation of growth hormone expression by Delta-like protein 1 (Dlk1). Molecular and cellular endocrinology 36 17485162
2020 Striatal glutamate delta-1 receptor regulates behavioral flexibility and thalamostriatal connectivity. Neurobiology of disease 33 31945419
2012 Pref-1 in brown adipose tissue: specific involvement in brown adipocyte differentiation and regulatory role of C/EBPδ. The Biochemical journal 29 22324440
1996 Characterization of Pref-1 and its inhibitory role in adipocyte differentiation. International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity 29 8680480
2022 Epigenome editing reveals core DNA methylation for imprinting control in the Dlk1-Dio3 imprinted domain. Nucleic acids research 28 35544282
2021 Dlk1 dosage regulates hippocampal neurogenesis and cognition. Proceedings of the National Academy of Sciences of the United States of America 28 33712542
2014 RHGF-1/PDZ-RhoGEF and retrograde DLK-1 signaling drive neuronal remodeling on microtubule disassembly. Proceedings of the National Academy of Sciences of the United States of America 28 25359212
2011 DLK1, delta-like 1 homolog (Drosophila), regulates tumor cell differentiation in vivo. Cancer letters 28 22142700
2018 A Hearty Dose of Noncoding RNAs: The Imprinted DLK1-DIO3 Locus in Cardiac Development and Disease. Journal of cardiovascular development and disease 26 29996488
2020 Astragalus Polysaccharide (PG2) Suppresses Macrophage Migration Inhibitory Factor and Aggressiveness of Lung Adenocarcinoma Cells. The American journal of Chinese medicine 24 32924531
2017 DLK1-DIO3 imprinted locus deregulation in development, respiratory disease, and cancer. Expert review of respiratory medicine 24 28715922
2008 Pref-1 and adipokine expression in adipose tissues of GK and Zucker rats. Molecular and cellular endocrinology 24 19084046
1998 Implication of ZOG protein (zona glomerulosa-specific protein) in zone development of the adrenal cortex. Endocrine research 24 9888532
2009 Expression regulation and function of Pref-1 during adipogenesis of human mesenchymal stem cells (MSCs). Biochimica et biophysica acta 23 19427405
2009 Isolation and differentiation of chondrocytic cells derived from human embryonic stem cells using dlk1/FA1 as a novel surface marker. Stem cell reviews and reports 22 20058200
2008 Expression of Dlk1 gene in myelodysplastic syndrome determined by microarray, and its effects on leukemia cells. International journal of molecular medicine 22 18575777
2024 A proteogenomic surfaceome study identifies DLK1 as an immunotherapeutic target in neuroblastoma. Cancer cell 21 39454577
2007 Expression of ksdD gene encoding 3-ketosteroid-Delta1-dehydrogenase from Arthrobacter simplex in Bacillus subtilis. Letters in applied microbiology 21 17451526
2014 Membrane-bound delta-like 1 homolog (Dlk1) promotes while soluble Dlk1 inhibits myogenesis in C2C12 cells. FEBS letters 20 24582655
1999 Genomic organization and genetic mapping of the bovine PREF-1 gene. Biochemical and biophysical research communications 19 10543989
2018 Glutamate delta-1 receptor regulates cocaine-induced plasticity in the nucleus accumbens. Translational psychiatry 18 30315226
2010 Expression of DLK1 and MEG3 genes in porcine tissues during postnatal development. Genetics and molecular biology 18 21637593
2008 Synergistic role of Igf2 and Dlk1 in fetal liver development and hematopoiesis in bi-maternal mice. The Journal of reproduction and development 18 18344616
2007 Expansion and characterization of ventral mesencephalic precursor cells: effect of mitogens and investigation of FA1 as a potential dopaminergic marker. Journal of neuroscience research 18 17471553
2016 A xylanase from Streptomyces sp. FA1: heterologous expression, characterization, and its application in Chinese steamed bread. Journal of industrial microbiology & biotechnology 17 26803505

Missed literature

Know a paper Affinage missed for DLK1? Flag it for the maintainers and the community.

No submissions yet.