Affinage

NEUROG3

Neurogenin-3 · UniProt Q9Y4Z2

Length
214 aa
Mass
23.1 kDa
Annotated
2026-06-10
92 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NEUROG3 (NGN3) is a basic helix-loop-helix transcription factor that acts as the master initiator of endocrine lineage specification in the pancreas and intestine (PMID:20025861, PMID:25650326). Its expression is set by a hierarchy of direct upstream activators that bind its promoter/enhancer — HNF-6/ONECUT1 (PMID:10825208), HNF1B (PMID:25715395), E2F1 acting in a CDK4-dependent manner (PMID:21490060), and STAT3 in response to inflammatory cytokines and in non-pancreatic contexts (PMID:22378757, PMID:27068459) — while GDF11/SMAD2 signaling restrains the size of the NGN3+ progenitor pool (PMID:15548585). Functioning as a pioneer transcription factor, NGN3 remodels chromatin accessibility and directly occupies promoters and enhancers of hundreds of target genes, including the endocrine transcription factors NEUROD1, PAX4, NKX2-2, RFX6/RFX3 and INSM2, and beta-cell functional genes such as GCK and ABCC8, thereby launching the islet gene program (PMID:16511571, PMID:20040487, PMID:21343251, PMID:34352411, PMID:40138419). Cell-fate output is dose-dependent: high NGN3 drives endocrine commitment whereas low levels permit ductal/acinar fates (PMID:20025861, PMID:25650326), and its pioneering activity is dose-tolerant such that NEUROD1 can substitute when NGN3 is absent, with the order of factor expression biasing alpha- versus beta-cell production (PMID:40138419). NGN3 protein abundance is tightly controlled post-translationally: CDK2/4/6 phosphorylate serine 183 to trigger proteasomal degradation, coupling endocrine differentiation to G1-phase lengthening (PMID:28441528); Notch/Hes1 signaling destabilizes the protein (PMID:23370147); and USP7 deubiquitinates and stabilizes it (PMID:37117185). In human progenitors NGN3 protein oscillates with ~13-hour periodicity, and these dynamics are decoded by fold-change detection through an incoherent feedforward loop to time differentiation (PMID:40570854). NGN3 in turn activates Dll1>Notch>Hes1 lateral inhibition to limit the number of cells entering the endocrine program and shape duct morphogenesis (PMID:21888903, PMID:23370147, PMID:30093553), and it is required for epithelial egression of nascent endocrine cells (PMID:30126902). Beyond initial specification, sustained NGN3 in hormone-expressing islet cells is needed for islet maturation and function (PMID:19487660). Biallelic loss-of-function mutations in human NEUROG3 cause neonatal diabetes with absent enteroendocrine cells (PMID:21378176).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2000 High

    Establishing how Neurog3 is switched on, HNF-6 was identified as the first direct upstream activator, anchoring the gene in a transcriptional hierarchy rather than acting in isolation.

    Evidence Promoter binding assay and hnf6-/- mouse with loss of Ngn3 expression

    PMID:10825208

    Open questions at the time
    • Did not identify the full set of cofactors at the Ngn3 promoter
    • Did not address post-transcriptional control of Ngn3
  2. 2004 High

    GDF11/SMAD2 signaling was shown to set the size of the NGN3+ progenitor pool, identifying an extrinsic brake on endocrine progenitor number.

    Evidence Gdf11-null and Smad2-null mice with progenitor quantification

    PMID:15548585

    Open questions at the time
    • Mechanistic link to Notch regulation only inferred
    • Did not define whether effect is on NGN3 transcription or progenitor proliferation
  3. 2006 High

    Direct chromatin binding at IA1, validated by epistasis against downstream factors, moved NGN3 from a presumed regulator to a demonstrated direct activator of early endocrine target genes.

    Evidence ChIP and ectopic expression in duct cells with genetic epistasis across multiple TF mutants

    PMID:16511571

    Open questions at the time
    • Single target locus, not genome-wide
    • Did not define cofactor requirements for activation
  4. 2008 Medium

    The mismatch between widespread Ngn3 mRNA and restricted protein revealed that post-transcriptional control, not just transcription, governs where NGN3 acts.

    Evidence Parallel mRNA in situ and protein immunofluorescence across embryogenesis; plus Myt1b/Ngn3 feed-forward loop by epistasis

    PMID:18394599 PMID:18924236

    Open questions at the time
    • Molecular mechanism of protein restriction not identified in these studies
    • Single-lab observations
  5. 2009 High

    Gene-dosage and conditional studies established that NGN3 level is a fate determinant and that its requirement extends beyond progenitor specification into islet maturation.

    Evidence Allelic dosage series with lineage tracking; conditional KO in hormone+ cells with reporter lines

    PMID:19487660 PMID:20025861

    Open questions at the time
    • Did not define the molecular threshold sensor
    • Mechanism of sustained maturation role left open
  6. 2010 High

    Defining the target hierarchy and the role of transcriptional activity, Rfx6 was placed directly downstream and NGN3's activation-domain strength was shown to switch cells between migration and differentiation.

    Evidence Epistasis in mutant embryos plus zebrafish loss-of-function; activation-domain mutant and VP16/EnR fusions in chick electroporation

    PMID:20040487 PMID:20549731

    Open questions at the time
    • Coactivators bridging NGN3 to target promoters not yet identified
    • Migration-versus-differentiation switch mechanism unresolved
  7. 2011 High

    Multiple studies cemented NGN3's direct target repertoire (Insm2), its requirement in humans, and its non-cell-autonomous role in feeding back via Notch to shape duct morphogenesis and limit endocrine commitment.

    Evidence ChIP and promoter mutagenesis (Insm2); human patient mutations with E-box binding and chick electroporation assays; Ngn3-null/gain-of-function morphogenesis; E2f1/Cdk4-dependent promoter activation

    PMID:21343251 PMID:21378176 PMID:21383077 PMID:21490060 PMID:21888903

    Open questions at the time
    • Direct ligand/receptor mediating the feedback signal not fully resolved
    • Genome-wide binding map still lacking at this point
  8. 2012 Medium

    A coactivator (CCAR1) and a context-specific upstream activator (STAT3 in spermatogonia) extended the regulatory and functional network around NGN3 beyond the pancreas.

    Evidence Reciprocal Co-IP/pull-down and reporter/knockdown for CCAR1; ChIP and RNAi/transplantation for STAT3

    PMID:22266316 PMID:22378757

    Open questions at the time
    • CCAR1 interaction from single lab without structural detail
    • Role of NGN3 outside endocrine tissues incompletely defined
  9. 2013 Medium

    Notch was shown to control NGN3 post-translationally by destabilizing the protein, distinguishing transcriptional from protein-level regulation in the lateral-inhibition circuit.

    Evidence Notch inhibition of pancreas explants with protein stability readout; conditional Ngn3 expression

    PMID:23370147

    Open questions at the time
    • Did not identify the degradation machinery
    • Single-lab pharmacological approach
  10. 2014 Medium

    Insm1 was found to support correct Neurog3 mRNA splicing/expression, adding an RNA-level layer to NGN3 control during progenitor differentiation.

    Evidence Insm1-null reporter mouse with transcriptomic analysis of progenitors

    PMID:25053427

    Open questions at the time
    • Direct splicing mechanism not demonstrated
    • Single-lab study
  11. 2015 High

    Human genetic and stem-cell models established the conserved, dose-dependent requirement of NEUROG3 for human endocrine development, and Hnf1b was confirmed as a direct upstream regulator.

    Evidence CRISPR knockout and knockdown titration in hESCs with in vitro/engraftment readouts; conditional Hnf1b KO with ChIP at Ngn3 locus

    PMID:25650326 PMID:25715395

    Open questions at the time
    • Why as little as 10% NGN3 suffices not mechanistically explained
    • Did not map genome-wide NGN3 targets in human cells
  12. 2016 Medium

    Inflammatory STAT3 signaling was shown to reactivate NGN3 and drive ductal-to-endocrine reprogramming, and a transcriptionally-active but low-protein progenitor state was defined, linking NGN3 level to proliferative versus committed states.

    Evidence Cytokine/STAT3 manipulation in ductal cells and NOD mice; BAC reporter with lineage tracing and mitotic index

    PMID:27068459 PMID:27585590

    Open questions at the time
    • Stability of reprogrammed endocrine cells not established
    • Single-lab reporter system
  13. 2017 High

    The S183 phosphodegron and its CDK2/4/6 writers were identified, mechanistically coupling NGN3 protein stability to cell-cycle state and explaining how G1 lengthening initiates differentiation; Nkx2.2 was placed downstream within the NGN3 lineage.

    Evidence Phospho-specific antibodies, S183 mutagenesis, CDK inhibition in mouse/human models; Neurog3-Cre lineage-specific Nkx2.2 KO

    PMID:28071588 PMID:28441528

    Open questions at the time
    • E3 ligase mediating S183-dependent degradation not identified here
    • Did not address deubiquitination counterbalance
  14. 2018 High

    Studies connected NGN3 to epithelial morphogenesis and established it as the effector driving Hes1-loss dysgenesis, showing NGN3 both responds to and remodels tissue architecture.

    Evidence ROCK/nmMyoII inhibition with live imaging and Ngn3-null; Hes1-/-;Neurog3-/- double-mutant epistasis with RNA-seq

    PMID:30093553 PMID:30126902

    Open questions at the time
    • Direct molecular link between NGN3 and the cell-detachment machinery undefined
    • Morphogenetic role single-lab for nmMyoII arm
  15. 2019 High

    An NGN3-independent epigenetic prepattern (Arx enhancer methylation) was shown to bias alpha- versus beta-cell fate before NGN3 acts, delineating the boundary of NGN3's instructive role.

    Evidence scRNA-seq, combinatorial lineage tracing, DNMT perturbation, locus-specific methylation analysis

    PMID:30620902

    Open questions at the time
    • How NGN3 integrates with the pre-set methylation state not resolved
    • Upstream determinant of differential Dnmt1 levels unknown
  16. 2021 High

    Genome-wide occupancy mapping in human progenitors converted the piecemeal target list into a defined direct regulatory network and consensus motif, distinguishing direct from indirect targets.

    Evidence CUT&RUN with HA-tagged NEUROG3 in hiPSC progenitors integrated with NEUROG3-/- transcriptomics

    PMID:34352411

    Open questions at the time
    • Functional weight of individual binding sites untested
    • Did not directly demonstrate chromatin remodeling at bound sites
  17. 2023 High

    USP7 was identified as the deubiquitinase that stabilizes NGN3, providing the counterweight to phosphodegron-driven turnover and a tractable node for controlling endocrine specification.

    Evidence Co-IP, deubiquitination assay, conditional Usp7 pancreas KO, and USP7 inhibition in human iPSC beta-cell differentiation

    PMID:37117185

    Open questions at the time
    • The cognate E3 ubiquitin ligase opposing USP7 not identified
    • Coupling between USP7 and S183 phosphorylation not resolved
  18. 2025 High

    NGN3 protein dynamics and chromatin function were defined: ~13h oscillations decoded by fold-change detection time differentiation, and NGN3 acts as a dose-tolerant pioneer factor whose expression order with NeuroD1 dictates alpha/beta-cell output.

    Evidence Endogenous knockin reporter with live imaging, protein stabilization, and mathematical modeling; ATAC-seq, binding mapping and sequential TF expression in mouse model

    PMID:40138419 PMID:40570854

    Open questions at the time
    • Molecular machinery generating the oscillation not fully defined
    • How fold-change is sensed at the chromatin level unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The full degradation machinery (E3 ligase) acting on phospho-S183 NGN3, and how oscillatory protein dynamics are mechanistically read out at target chromatin to set the differentiation threshold, remain open.
  • No E3 ligase opposing USP7 identified
  • Chromatin-level decoder of fold-change detection unknown
  • Quantitative link between protein threshold and individual target activation undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 5 GO:0140110 transcription regulator activity 4
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-4839726 Chromatin organization 1
Partners
CCAR1USP7

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 HNF-6 (ONECUT1) directly binds to and activates the ngn3 gene promoter, establishing HNF-6 as the first identified positive transcriptional regulator of Neurog3 in the developing pancreas. Loss of HNF-6 in mice nearly abolishes Ngn3 expression and impairs endocrine cell differentiation. Promoter binding assay, mouse knockout (hnf6-/-), expression analysis Molecular and cellular biology High 10825208
2006 Ngn3 directly binds chromatin at the IA1 promoter and activates IA1 transcription in adult pancreatic duct cells. IA1 expression is absent in Ngn3-null embryos but is normal in embryos mutant for downstream factors (NeuroD1, Arx, Pax4, Pax6), placing IA1 as a direct, early Ngn3 target gene. Chromatin immunoprecipitation (ChIP), ectopic Ngn3 expression in adult duct cells, genetic epistasis in multiple transcription factor mutant embryos The EMBO journal High 16511571
2008 Ngn3 protein exhibits biphasic expression during mouse pancreatic development (E8.5–E11.0 first wave; E12.0 onward second wave), and Ngn3 transcripts are markedly more widespread than NGN3 protein in the pancreatic epithelium, indicating substantial post-transcriptional regulation of Ngn3. mRNA in situ hybridization, immunofluorescence protein detection throughout embryonic development Developmental dynamics Medium 18924236
2008 Myt1b and Ngn3 form a feed-forward expression loop: Myt1b potentiates Ngn3 transcription in pancreatic progenitors, and Ngn3 protein production in turn induces Myt1 expression. Pancreatic Myt1 expression largely depends on Ngn3 activity. Gain-of-function overexpression, analysis of Ngn3-null mutant pancreata, expression profiling Developmental biology Medium 18394599
2009 Neurog3 mRNA and protein are present not only in endocrine progenitors but also in hormone-expressing islet cells (embryonic and adult). Conditional inactivation of Neurog3 in insulin-expressing beta cells or Pdx1-expressing islet cells impairs endocrine function and reduces expression of Neurog3 target genes required for islet maturation, demonstrating that sustained Neurog3 expression is required for islet maturation and function beyond its progenitor role. Neurog3 knock-in reporter mice (3 independent lines), mRNA/protein assays, conditional knockout (Cre-lox) Proceedings of the National Academy of Sciences of the United States of America High 19487660
2009 Neurog3 gene dosage directly controls endocrine commitment: high levels of Neurog3 are required for endocrine fate specification from multipotent pancreatic progenitors, while reduced Neurog3 expression causes progenitors to adopt ductal or acinar fates instead. Neurog3 heterozygosity and hypomorphic allele (gene-dosage manipulation), lineage analysis, cell fate tracking Developmental biology High 20025861
2010 Rfx6 is transcriptionally downstream of Ngn3: Rfx6 expression is lost in Ngn3-null mice and is maintained in embryos lacking NeuroD, Pax4, and Arx, placing Rfx6 directly below Ngn3 in the endocrine differentiation hierarchy. Loss-of-function studies in zebrafish show Rfx6 is required for differentiation of glucagon-, ghrelin-, and somatostatin-expressing cells. Gene expression profiling of isolated Ngn3+ progenitors, analysis in Ngn3-null and other transcription factor mutant embryos (epistasis), zebrafish loss-of-function Development (Cambridge, England) High 20040487
2011 NEUROG3 is required for endocrine pancreas and enteroendocrine cell development in humans: biallelic loss-of-function mutations (including a nonsense mutation E28X and a missense L135P) abolish NEUROG3 binding to the NEUROD1 promoter E-box in vitro and eliminate its ability to induce ectopic endocrine cell formation and delamination in chicken endoderm electroporation assays. Patients with null mutations lack enteroendocrine cells entirely and develop neonatal diabetes. In vitro E-box binding assay (NEUROD1 promoter), in ovo chicken endoderm electroporation, intestinal biopsy immunostaining Diabetes High 21378176
2011 Ngn3-expressing endocrine progenitor cells provide a cell-extrinsic feedback signal to adjacent multipotent ductal progenitor cells that activates Notch signaling, limiting further endocrine differentiation and promoting proper duct morphogenesis. Ngn3-/- mice have reduced branching and enlarged duct-like structures, and forced surplus endocrine progenitors reduce duct caliber. Ngn3 knockout mouse analysis, forced endocrine progenitor generation, Notch signaling measurement Developmental biology Medium 21888903
2011 ATOH1/MATH1 is essential for intestinal tuft cell differentiation whereas Neurog3 is dispensable for tuft cell fate, distinguishing tuft cells from enteroendocrine cells (which require Neurog3). Conditional knockout mouse models (Neurog3-null, ATOH1-null), immunostaining for tuft cell markers The Journal of cell biology Medium 21383077
2011 Mutagenesis and chromatin immunoprecipitation demonstrate that Ngn3 directly targets the proximal E-boxes of the Insm2 promoter. Endogenous Insm2 expression is activated in Ngn3/NeuroD1-transduced pancreatic epithelial duct cells, establishing Insm2 as a direct transcriptional target of Ngn3. Promoter mutagenesis, chromatin immunoprecipitation (ChIP), ectopic Ngn3/NeuroD1 expression in pancreatic duct cells Endocrinology High 21343251
2012 CCAR1 physically interacts with Ngn3 (verified by pull-down and co-immunoprecipitation) and is required as a coactivator for Ngn3 to activate NeuroD promoter-driven reporter gene expression. Knockdown of endogenous CCAR1 in PANC-1 cells inhibits Ngn3-initiated transdifferentiation toward endocrine fate. Pulldown assay, co-immunoprecipitation, luciferase reporter assay, siRNA knockdown Biochemical and biophysical research communications Medium 22266316
2012 STAT3 directly binds the distal Neurog3 promoter/enhancer region in THY1+ spermatogonia and regulates Neurog3 transcription. GDNF (a self-renewal factor for spermatogonial stem cells) suppresses STAT3 activation and consequently represses Neurog3 expression. Transient inhibition of Neurog3 in spermatogonia impairs SSC differentiation in vitro and in vivo transplantation assays. ChIP (STAT3 at Neurog3 promoter), pharmacological JAK/STAT inhibition, RNAi knockdown, transplantation assay Biology of reproduction High 22378757
2013 Notch signaling regulates Ngn3 not only at the transcriptional level but also via a post-translational mechanism: Notch>Hes1 pathway activation destabilizes Ngn3 protein. Inhibition of Notch signaling in mouse pancreas explants leads to Ngn3 protein stabilization. Ngn3 also cell-extrinsically activates the Dll1>Notch>Hes1 lateral inhibition pathway, which feeds back to limit endocrine differentiation. Conditional Ngn3 expression in pancreas, Notch inhibitor treatment of pancreas explants, protein stability assays Developmental biology Medium 23370147
2014 Insm1 positively regulates Neurog3: embryos lacking Insm1 contain greater amounts of a non-coding Neurog3 mRNA splice variant and have fewer Neurog3/Insm1 co-expressing progenitor cells, suggesting Insm1 modulates correct Neurog3 mRNA splicing/expression during endocrine progenitor differentiation. Insm1 GFP-Cre reporter knock-in mouse, transcriptomic analysis of Insm1-null endocrine progenitors, expression profiling Development (Cambridge, England) Medium 25053427
2015 NEUROG3 is required for human endocrine pancreas development: CRISPR/Cas9 biallelic disruption of NEUROG3 in human ESCs blocks endocrine cell formation both in vitro and after engraftment in mice. A 75–90% knockdown of NEUROG3 reduces but does not eliminate endocrine cell formation, and as little as 10% NEUROG3 is sufficient for endocrine cell production. CRISPR/Cas9 gene targeting in hESCs, in vitro differentiation, mouse engraftment, NEUROG3 knockdown titration Diabetes High 25650326
2015 Hnf1b occupies Ngn3 putative regulatory sequences in vivo, and inactivation of Hnf1b at different embryonic time points results in absence of Ngn3+ endocrine precursors throughout embryogenesis, establishing Hnf1b as a direct upstream regulator required for endocrine progenitor generation. Constitutive and inducible conditional Hnf1b knockout mice, ChIP for Hnf1b at Ngn3 regulatory sequences, endocrine precursor quantification Development (Cambridge, England) High 25715395
2016 Inflammatory cytokines activate NGN3 expression in pancreatic ductal cells via STAT3 signaling, driving ductal-to-endocrine cell reprogramming both in vitro (human ductal cell line and mouse ductal cells) and in vivo (intraductal injection, NOD mouse autoimmune diabetes model). Cytokine treatment of human ductal cell line, pancreatic intraductal injection in mice, NOD mouse model, STAT3 inhibition Cell reports Medium 27068459
2016 A mitotic Neurog3-transcriptionally-active but low-protein (Neurog3TA.LO) cell population in Sox9+ epithelium represents an endocrine-biased progenitor state with prolonged epithelial residency and high mitotic index, functionally separated from the endocrine-committed Neurog3HI state. Limiting Neurog3 expression doubles the mitotic index of this progenitor pool. BAC transgenic Neurog3 reporter, lineage tracing, mitotic index measurement, Neurog3 dose manipulation Genes & development Medium 27585590
2017 NEUROG3 is phosphorylated on serine 183 within the nucleus, which catalyzes its hyperphosphorylation and proteasomal degradation. This phosphorylation is driven by cyclin-dependent kinases 2 and 4/6 at the G1/S cell-cycle checkpoint. G1-phase lengthening in pancreatic progenitors stabilizes NEUROG3 and is essential for initiating endocrine differentiation. Phospho-specific antibodies, site-directed mutagenesis (S183), CDK inhibitor treatment, mouse and human pancreas development models, cell-cycle manipulation Developmental cell High 28441528
2017 Nkx2.2 functions downstream of Neurog3: conditional ablation of Nkx2.2 specifically in the Neurog3+ endocrine progenitor lineage (using Neurog3-Cre) recapitulates the full Nkx2.2-null β-cell differentiation defect, demonstrating that Nkx2.2's essential activity for β-cell specification occurs within the Neurog3+ progenitor population. Conditional knockout using Neurog3-Cre, comparison of Nkx2.2 whole-body null vs. lineage-specific null phenotypes eLife High 28071588
2018 The ROCK-nmMyoII pathway coordinates epithelial morphogenesis with Neurog3 expression: nmMyoII is necessary for apical narrowing, basalward cell displacement, and Neurog3 transcriptional upregulation, but all three are limited by ROCK activity. Neurog3 protein is required for cell-rear detachment and complete endocrine-cell birth from the epithelial plexus. Pharmacological ROCK/nmMyoII inhibition, Neurog3-null analysis, live imaging of epithelial egression Development (Cambridge, England) Medium 30126902
2018 Hes1 loss causes ectopic pancreas through Neurog3-dependent mechanisms: genetic inactivation of Neurog3 in a Hes1-null background normalizes early pancreas morphogenesis and suppresses the ectopic pancreas phenotype, demonstrating that aberrant upregulation of Neurog3-driven endocrine differentiation drives the dysgenesis. Double mutant epistasis (Hes1-/-; Neurog3-/-), lineage tracing, live imaging, RNA-seq of sorted cells Development (Cambridge, England) High 30093553
2018 NGN3 loss-of-function in pigs (CRISPR/Cas9 biallelic knockout) eliminates expression of downstream target genes NEUROD1 and PAX4, and abolishes insulin, glucagon, somatostatin, and pancreatic polypeptide-Y, confirming NGN3's conserved essential role in porcine endocrine pancreas development. CRISPR/Cas9 gene ablation in pigs, immunostaining and gene expression analysis of NGN3 knockout fetuses and neonates Scientific reports High 29483633
2019 Neurog3-independent DNA methylation at the Arx enhancer in pancreatic progenitors pre-specifies endocrine cell type fate: progenitors with higher Dnmt1 expression and Arx enhancer hypermethylation are biased toward β-cell fate, while those with lower methylation favor α-cell fate. This methylation state is established before Neurog3 activation and is not determined by Neurog3 itself. Single-cell RNA-seq, trajectory analysis, combinatorial lineage tracing (Myt1+Neurog3+ vs Myt1-Neurog3+), DNMT inhibition, Dnmt1 overexpression, targeted Arx enhancer methylation analysis Developmental cell High 30620902
2021 Genome-wide NEUROG3 occupancy mapping (CUT&RUN) in human iPSC-derived endocrine progenitors identified 863 binding sites assigned to 1263 genes, with a defined consensus NEUROG3 binding motif. NEUROG3 directly occupies promoters and enhancers of transcription factors essential for islet development (NEUROD1, PAX4, NKX2-2, SOX4, RFX3, NEUROG3 itself) and genes critical for beta-cell function (GCK, ABCC8/KCNJ11, CACNA1A, SLC30A8, PCSK1). 22% of genes downregulated in NEUROG3-/- progenitors are directly bound by NEUROG3. CUT&RUN chromatin occupancy mapping, hiPSC differentiation with HA-tagged NEUROG3, de novo motif analysis, integration with NEUROG3-/- transcriptomics Molecular metabolism High 34352411
2023 USP7 (a deubiquitylating enzyme) physically interacts with, deubiquitinates, and stabilizes NGN3 protein. Conditional knockout of Usp7 in mouse embryonic pancreas dramatically reduces islet formation and causes adult hyperglycemia by impairing NGN3-mediated endocrine specification. Pharmacological inhibition of USP7 during human iPSC-derived beta-cell differentiation decreases NGN3+ progenitor numbers and impairs beta-cell differentiation. Binding partner screen, co-immunoprecipitation, deubiquitination assay, conditional Usp7 knockout in pancreas (Cre-lox), human iPSC differentiation with USP7 inhibitor Nature communications High 37117185
2025 NGN3 protein oscillates with ~13-hour periodicity in human iPSC-derived endocrine progenitors and is extinguished upon differentiation. Stabilizing NGN3 protein (increasing protein stability) converts oscillations to a single broad peak and causes precocious endocrine differentiation and earlier expression of NGN3 target genes. Mathematical modeling and experimental validation indicate NGN3 oscillations are decoded via fold-change detection (FCD) through an incoherent feedforward loop (IFFL) motif. Knockin endogenous NGN3 reporter in hiPSCs, live imaging, protein stability manipulation, single-cell dynamics analysis, mathematical modeling Developmental cell High 40570854
2025 NGN3 functions as a pioneer transcription factor that remodels chromatin accessibility during pancreatic endocrine differentiation. NGN3's pioneering function exhibits dose tolerance (low doses are sufficient). In the absence of NGN3, NEUROD1 can assume a pioneering role. Sequential expression of NeuroD1 before Ngn3 predominantly drives α-cell generation, explaining inefficient β-cell induction in certain in vitro contexts. Genetically engineered mouse model, NGN3 ChIP/binding site mapping, ATAC-seq (chromatin accessibility), manipulation of TF expression order Science advances High 40138419
2010 Ectopic Neurog3 in chicken endoderm requires full transcriptional activity for migration of electroporated cells: fusing Neurog3 to VP16 or co-electroporation with Ep300 (increased transcriptional activity) causes cells to migrate rather than differentiate, while reducing transcriptional activity (deletion of activation domain, engrailed repressor fusion, Hdac1 co-expression) greatly increases glucagon-expressing cell production. In ovo chicken endoderm electroporation, Neurog3 activation-domain deletion mutants, Neurog3-VP16 and Neurog3-EnR fusions, co-electroporation with Ep300 or Hdac1 Developmental dynamics Medium 20549731
2011 E2f1 binds and activates the Ngn3 promoter in a Cdk4-dependent manner in the embryonic pancreas. Expression of activated Cdk4(R24C) kinase increases the number and proliferation of Ngn3+ endocrine precursors, leading to β-cell expansion. ChIP (E2f1 at Ngn3 promoter), Cdk4 knockout and Cdk4(R24C) gain-of-function mouse models, Ngn3+ cell quantification Development (Cambridge, England) High 21490060
2004 GDF11 (acting through SMAD2) negatively regulates the number of NGN3+ islet progenitor cells in the mouse pancreas. Gdf11-null mice have increased NGN3+ cell numbers but reduced beta-cell numbers, indicating GDF11/SMAD2 signaling controls both progenitor pool size and beta-cell maturation downstream or in parallel with Notch pathway regulation of NGN3+ cells. Gdf11-null and Smad2-null mouse analysis, NGN3+ cell quantification, beta-cell counting Development (Cambridge, England) High 15548585

Source papers

Stage 0 corpus · 92 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Distinct ATOH1 and Neurog3 requirements define tuft cells as a new secretory cell type in the intestinal epithelium. The Journal of cell biology 319 21383077
2000 Transcription factor hepatocyte nuclear factor 6 regulates pancreatic endocrine cell differentiation and controls expression of the proendocrine gene ngn3. Molecular and cellular biology 275 10825208
2017 Fasting-Mimicking Diet Promotes Ngn3-Driven β-Cell Regeneration to Reverse Diabetes. Cell 264 28235195
2017 Genetic evidence that Nkx2.2 acts primarily downstream of Neurog3 in pancreatic endocrine lineage development. eLife 156 28071588
2005 PDX-1/VP16 fusion protein, together with NeuroD or Ngn3, markedly induces insulin gene transcription and ameliorates glucose tolerance. Diabetes 151 15793239
2006 IA1 is NGN3-dependent and essential for differentiation of the endocrine pancreas. The EMBO journal 149 16511571
2009 Sustained Neurog3 expression in hormone-expressing islet cells is required for endocrine maturation and function. Proceedings of the National Academy of Sciences of the United States of America 142 19487660
2004 GDF11 modulates NGN3+ islet progenitor cell number and promotes beta-cell differentiation in pancreas development. Development (Cambridge, England) 134 15548585
2010 Rfx6 is an Ngn3-dependent winged helix transcription factor required for pancreatic islet cell development. Development (Cambridge, England) 126 20040487
2011 Permanent Neonatal Diabetes and Enteric Anendocrinosis Associated With Biallelic Mutations in NEUROG3. Diabetes 116 21378176
2008 Biphasic Ngn3 expression in the developing pancreas. Developmental dynamics : an official publication of the American Association of Anatomists 112 18924236
2009 Neurog3 gene dosage regulates allocation of endocrine and exocrine cell fates in the developing mouse pancreas. Developmental biology 110 20025861
2015 Hnf1b controls pancreas morphogenesis and the generation of Ngn3+ endocrine progenitors. Development (Cambridge, England) 103 25715395
2015 The Basic Helix-Loop-Helix Transcription Factor NEUROG3 Is Required for Development of the Human Endocrine Pancreas. Diabetes 92 25650326
2012 Reprogramming of pancreatic exocrine cells towards a beta (β) cell character using Pdx1, Ngn3 and MafA. The Biochemical journal 88 22150363
2008 Myt1 and Ngn3 form a feed-forward expression loop to promote endocrine islet cell differentiation. Developmental biology 74 18394599
2021 Ductal Ngn3-expressing progenitors contribute to adult β cell neogenesis in the pancreas. Cell stem cell 73 34478642
2017 Phosphorylation of NEUROG3 Links Endocrine Differentiation to the Cell Cycle in Pancreatic Progenitors. Developmental cell 71 28441528
2006 Ngn3 expression during postnatal in vitro beta cell neogenesis induced by the JAK/STAT pathway. Cell death and differentiation 69 16514419
2005 Enhanced expression of PDX-1 and Ngn3 by exendin-4 during beta cell regeneration in STZ-treated mice. Biochemical and biophysical research communications 67 15652518
2012 NEUROG3 is a critical downstream effector for STAT3-regulated differentiation of mammalian stem and progenitor spermatogonia. Biology of reproduction 64 22378757
2016 Proinflammatory Cytokines Induce Endocrine Differentiation in Pancreatic Ductal Cells via STAT3-Dependent NGN3 Activation. Cell reports 62 27068459
2011 Ngn3(+) endocrine progenitor cells control the fate and morphogenesis of pancreatic ductal epithelium. Developmental biology 60 21888903
2014 Insm1 promotes endocrine cell differentiation by modulating the expression of a network of genes that includes Neurog3 and Ripply3. Development (Cambridge, England) 58 25053427
2011 Hormonally defined pancreatic and duodenal neuroendocrine tumors differ in their transcription factor signatures: expression of ISL1, PDX1, NGN3, and CDX2. Virchows Archiv : an international journal of pathology 54 21739268
2016 Precommitment low-level Neurog3 expression defines a long-lived mitotic endocrine-biased progenitor pool that drives production of endocrine-committed cells. Genes & development 52 27585590
2007 Novel effectors of directed and Ngn3-mediated differentiation of mouse embryonic stem cells into endocrine pancreas progenitors. Stem cells (Dayton, Ohio) 49 17932425
2013 Notch-mediated post-translational control of Ngn3 protein stability regulates pancreatic patterning and cell fate commitment. Developmental biology 44 23370147
2021 Breast milk MSCs upregulated β-cells PDX1, Ngn3, and PCNA expression via remodeling ER stress /inflammatory /apoptotic signaling pathways in type 1 diabetic rats. European journal of pharmacology 42 34004210
2019 Neurog3-Independent Methylation Is the Earliest Detectable Mark Distinguishing Pancreatic Progenitor Identity. Developmental cell 40 30620902
2011 Pdx1 and Ngn3 overexpression enhances pancreatic differentiation of mouse ES cell-derived endoderm population. PloS one 38 21931641
2011 The Cdk4-E2f1 pathway regulates early pancreas development by targeting Pdx1+ progenitors and Ngn3+ endocrine precursors. Development (Cambridge, England) 37 21490060
2013 Reprogramming of various cell types to a beta-like state by Pdx1, Ngn3 and MafA. PloS one 35 24312421
2011 PDX1- and NGN3-mediated in vitro reprogramming of human bone marrow-derived mesenchymal stromal cells into pancreatic endocrine lineages. Cytotherapy 35 21506889
2013 Ascl1b and Neurod1, instead of Neurog3, control pancreatic endocrine cell fate in zebrafish. BMC biology 34 23835295
2009 5'-AZA induces Ngn3 expression and endocrine differentiation in the PANC-1 human ductal cell line. Biochemical and biophysical research communications 32 19913512
2008 Mouse pancreatic endocrine cell transcriptome defined in the embryonic Ngn3-null mouse. Diabetes 31 18599526
2021 Extensive NEUROG3 occupancy in the human pancreatic endocrine gene regulatory network. Molecular metabolism 28 34352411
2012 The combined expression of Pdx1 and MafA with either Ngn3 or NeuroD improves the differentiation efficiency of mouse embryonic stem cells into insulin-producing cells. Cell transplantation 28 22776709
2011 Streptozotocin-induced expression of Ngn3 and Pax4 in neonatal rat pancreatic α-cells. World journal of gastroenterology 28 21734788
2016 Reprogramming of Pancreatic Exocrine Cells AR42J Into Insulin-producing Cells Using mRNAs for Pdx1, Ngn3, and MafA Transcription Factors. Molecular therapy. Nucleic acids 27 27187823
2023 Matters arising: Insufficient evidence that pancreatic β cells are derived from adult ductal Neurog3-expressing progenitors. Cell stem cell 23 37028408
2018 Targeted Mutation of NGN3 Gene Disrupts Pancreatic Endocrine Cell Development in Pigs. Scientific reports 23 29483633
2015 Bicaudal C1 promotes pancreatic NEUROG3+ endocrine progenitor differentiation and ductal morphogenesis. Development (Cambridge, England) 23 25715394
2014 Prospectively isolated NGN3-expressing progenitors from human embryonic stem cells give rise to pancreatic endocrine cells. Stem cells translational medicine 20 24493854
2010 In vitro expression of NGN3 identifies RAB3B as the predominant Ras-associated GTP-binding protein 3 family member in human islets. The Journal of endocrinology 20 20807725
2020 Reduced Neurog3 Gene Dosage Shifts Enteroendocrine Progenitor Towards Goblet Cell Lineage in the Mouse Intestine. Cellular and molecular gastroenterology and hepatology 19 32822913
2018 ROCK-nmMyoII, Notch and Neurog3 gene-dosage link epithelial morphogenesis with cell fate in the pancreatic endocrine-progenitor niche. Development (Cambridge, England) 17 30126902
2016 An inhibitor of fibroblast growth factor receptor-1 (FGFR1) promotes late-stage terminal differentiation from NGN3+ pancreatic endocrine progenitors. Scientific reports 16 27786288
2017 A novel NEUROG3 mutation in neonatal diabetes associated with a neuro-intestinal syndrome. Pediatric diabetes 15 28940958
2011 Expression of insulinoma-associated 2 (INSM2) in pancreatic islet cells is regulated by the transcription factors Ngn3 and NeuroD1. Endocrinology 15 21343251
2019 Pax4 synergistically acts with Pdx1, Ngn3 and MafA to induce HuMSCs to differentiate into functional pancreatic β-cells. Experimental and therapeutic medicine 14 31572507
2015 Pdxl and its role in activating Ngn3 and Pax6 to induce differentiation of iPSCs into islet β cells. Genetics and molecular research : GMR 14 26345820
2023 USP7 controls NGN3 stability and pancreatic endocrine lineage development. Nature communications 13 37117185
2020 Estradiol-dependent axogenesis and Ngn3 expression are determined by XY sex chromosome complement in hypothalamic neurons. Scientific reports 13 32427857
2001 Mutations in the coding region of the neurogenin 3 gene (NEUROG3) are not a common cause of maturity-onset diabetes of the young in Japanese subjects. Diabetes 13 11246894
2020 Null mutations of NEUROG3 are associated with delayed-onset diabetes mellitus. JCI insight 12 31805014
2018 Neurog3-dependent pancreas dysgenesis causes ectopic pancreas in Hes1 mutant mice. Development (Cambridge, England) 12 30093553
2012 Transient expression of Ngn3 in Xenopus endoderm promotes early and ectopic development of pancreatic beta and delta cells. Genesis (New York, N.Y. : 2000) 12 22121111
2012 CCAR1 is required for Ngn3-mediated endocrine differentiation. Biochemical and biophysical research communications 11 22266316
2022 Expression Profiling of Pdx1, Ngn3, and MafA in the Liver and Pancreas of Recovering Streptozotocin-Induced Diabetic Rats. Genes 10 36140793
2025 NGN3 oscillatory expression controls the timing of human pancreatic endocrine differentiation. Developmental cell 9 40570854
2013 Expression pattern of Ngn3 in dairy goat testis and its function in promoting meiosis by upregulating Stra8. Cell proliferation 9 24450812
2006 NEUROG3 variants and type 2 diabetes in Italians. Minerva medica 9 17146417
2010 The transcriptional activity of Neurog3 affects migration and differentiation of ectopic endocrine cells in chicken endoderm. Developmental dynamics : an official publication of the American Association of Anatomists 8 20549731
2024 Forward programming of hiPSCs towards beta-like cells using Ngn3, Pdx1, and MafA. Scientific reports 7 38871849
2022 Carob extract induces spermatogenesis in an infertile mouse model via upregulation of Prm1, Plzf, Bcl-6b, Dazl, Ngn3, Stra8, and Smc1b. Journal of ethnopharmacology 7 36209951
2017 Reprogramming of Pancreatic Acinar Cells to Functional Beta Cells by In Vivo Transduction of a Polycistronic Construct Containing Pdx1, Ngn3, MafA in Mice. Current protocols in stem cell biology 7 28152182
2017 Pancreatic islet regeneration through PDX-1/Notch-1/Ngn3 signaling after gastric bypass surgery in db/db mice. Experimental and therapeutic medicine 7 28966671
2022 Novel Variants and Phenotypes in NEUROG3-Associated Syndrome. The Journal of clinical endocrinology and metabolism 6 36149814
2021 Effect of NEUROG3 polymorphism rs144643855 on regional spontaneous brain activity in major depressive disorder. Behavioural brain research 6 33878431
2018 Neurog3 misexpression unravels mouse pancreatic ductal cell plasticity. PloS one 6 30092080
2025 The expression order determines the pioneer functions of NGN3 and NEUROD1 in pancreatic endocrine differentiation. Science advances 5 40138419
2024 A hydrolyzed casein diet promotes Ngn3 controlling enteroendocrine cell differentiation to increase gastrointestinal motility in mice. Food & function 5 38227487
2021 Ngn3-Positive Cells Arise from Pancreatic Duct Cells. International journal of molecular sciences 5 34445257
2017 Changes on the Pancreas in Experimental Diabetes and the Effect of Lycopene on These Changes: Pdx-1, Ngn-3, and Nestin Expressions. Anatomical record (Hoboken, N.J. : 2007) 5 28921917
2016 Adult human pancreas-derived cells expressing stage-specific embryonic antigen 4 differentiate into Sox9-expressing and Ngn3-expressing pancreatic ducts in vivo. Stem cell research & therapy 4 27836003
2008 Bipotential mouse embryonic liver (BMEL) cells spontaneously express Pdx1 and Ngn3 but do not undergo further pancreatic differentiation upon Hes1 down-regulation. BMC research notes 4 19108739
2007 Co-expressing Pdx1 and Ngn3 induces few beta-like cells in the liver of mice. Biochemical and biophysical research communications 4 17706592
2025 Ductal or Ngn3+ cells do not contribute to adult pancreatic islet beta-cell neogenesis in homeostasis. The EMBO journal 3 40205162
2022 The Roles of Different Multigene Combinations of Pdx1, Ngn3, Sox9, Pax4, and Nkx2.2 in the Reprogramming of Canine ADSCs Into IPCs. Cell transplantation 3 35236160
2021 Protein Production and Purification of a Codon-Optimized Human NGN3 Transcription Factor from E. coli. The protein journal 3 34550497
2017 FUCCI tracking shows cell-cycle-dependent Neurog3 variation in pancreatic progenitors. Genesis (New York, N.Y. : 2000) 3 28772022
2011 Pdx1- and Ngn3-Cre-mediated PLAG1 expression in the pancreas leads to endocrine hormone imbalances that affect glucose metabolism. Cell transplantation 3 21294959
2020 Transient FOXO1 inhibition in pancreatic endoderm promotes the generation of NGN3+ endocrine precursors from human iPSCs. Stem cell research 2 32179491
2023 Single-cell transcriptome analysis of NEUROG3+ cells during pancreatic endocrine differentiation with small molecules. Stem cell research & therapy 1 37098639
2010 [Construction and identification of recombinant retroviral vector of human ngn3 gene and its packaging cell line]. Sheng wu gong cheng xue bao = Chinese journal of biotechnology 1 20575431
2026 Epigenetic control of PDX1 and NGN3 by a computationally designed PRC2 inhibitor enforces pancreatic endocrine differentiation from pluripotent stem cells. Research square 0 41928786
2026 Ngn3 Regulates Differentiation Competence of Retinal Progenitor Cells Through Transcriptional and Epigenetic Modification. International journal of molecular sciences 0 42123429
2025 Innovative therapeutic modalities of purified platelet-derived growth factors on PDX1, Neurog3, and renin expressions in STZ-induced diabetic nephropathy and pancreatic injury. Life sciences 0 40834996
2025 NEUROG3 Is Sufficient to Drive Neuroendocrine Differentiation in Prostate Cancer Cells. bioRxiv : the preprint server for biology 0 41293011
2005 [In vitro evidence for pancreatic lineage: Ngn3 positive cells are endocrine progenitors derived from cultured islets]. Zhonghua wai ke za zhi [Chinese journal of surgery] 0 15774173

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