Affinage

PAX4

Paired box protein Pax-4 · UniProt O43316

Length
350 aa
Mass
37.8 kDa
Annotated
2026-06-10
100 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PAX4 is a paired-domain/homeodomain transcriptional repressor that specifies the beta- and delta-cell lineages of the endocrine pancreas from endocrine progenitors (PMID:9121556, PMID:14729487). It acts as an intrinsic repressor through its homeodomain and C-terminal domains, silencing the glucagon, insulin, and islet amyloid polypeptide promoters and negatively autoregulating its own promoter (PMID:10567552, PMID:10601637, PMID:10967107). Lineage allocation is governed by a mutually repressive antagonism between PAX4 and ARX: loss of one factor derepresses the other, with PAX4 driving beta/delta fate and ARX driving alpha fate, such that loss of both yields near-exclusive delta cells (PMID:14561778, PMID:15930104); this antagonism extends to enteroendocrine D/L cell allocation in the intestine (PMID:22570716). PAX4 also represses ghrelin to restrain epsilon-cell expansion (PMID:18058910, PMID:36897579). Its expression is induced developmentally by cooperative Neurogenin3–HNF1alpha synergy and by mitogenic and metabolic signals including activin A, SREBP1c, and adrenergic-cAMP cues (PMID:12837760, PMID:16546275, PMID:30352876, PMID:18818287). Beyond development, PAX4 is a beta-cell survival and proliferation factor that transactivates Bcl-xL and c-myc, preserves ER homeostasis and calcium handling, and protects against cytokine- and ER-stress-induced apoptosis (PMID:15596543, PMID:17260022, PMID:26813254). Ectopic PAX4 is sufficient to convert alpha and delta cells into functional beta-like cells and reverse chemically induced diabetes (PMID:19665969, PMID:29025873). In humans, loss-of-function and stability-impairing PAX4 variants cause neonatal diabetes and predispose to diabetes, with complete homozygous loss producing transient rather than permanent neonatal diabetes, indicating PAX4 is not absolutely essential for human beta-cell development (PMID:37777536, PMID:40614820, PMID:41475885).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1997 High

    Established the foundational developmental requirement for PAX4, answering whether it specifies particular endocrine lineages.

    Evidence Homozygous Pax4 knockout mice analyzed by immunohistochemistry

    PMID:9121556

    Open questions at the time
    • Did not define molecular targets or repressor mechanism
    • Did not address the reciprocal alpha-cell expansion mechanism
  2. 1999 High

    Resolved that PAX4 acts as an intrinsic transcriptional repressor, mapping the activity to discrete domains rather than mere competition with PAX6.

    Evidence Reporter assays, GAL4-PAX4 chimera domain mapping, and in vitro DNA binding in alpha/beta cell lines

    PMID:10364449 PMID:10567552 PMID:10567553 PMID:10601637

    Open questions at the time
    • Genome-wide target spectrum not defined
    • Co-repressor partners mediating repression not identified
    • Structural basis of homeodomain dimerization not solved
  3. 2000 High

    Defined how PAX4 transcription is controlled, identifying upstream activators and a negative autoregulatory loop.

    Evidence Transgenic reporter animals, deletion mapping, EMSA, footprinting and mutagenesis of the PAX4 promoter

    PMID:10967107 PMID:11162892

    Open questions at the time
    • Did not establish in vivo necessity of each binding site for endogenous expression
    • Chromatin context not addressed
  4. 2003 High

    Identified the PAX4–ARX mutual repression as the molecular switch for alpha versus beta/delta fate and identified Ngn3/HNF1alpha as cooperative inducers.

    Evidence Reciprocal knockout mice with transcript analysis; reporter/EMSA and physical interaction assays plus NRSE/NRSF studies

    PMID:12829700 PMID:12837760 PMID:14561778

    Open questions at the time
    • Direct evidence that PAX4 binds the Arx promoter in vivo not shown
    • Whether antagonism is direct or relayed through intermediates unresolved
  5. 2004 High

    Ordered PAX4 within the beta-cell differentiation hierarchy and linked it to proliferation/survival gene programs.

    Evidence Knockout epistasis with Nkx2.2 and Pdx1/HB9/insulin staining; adenoviral overexpression with Bcl-xL/c-myc reporter assays and mitochondrial calcium/ATP measurements

    PMID:14729487 PMID:15596543

    Open questions at the time
    • Direct PAX4 occupancy of Bcl-xL/c-myc promoters in vivo not confirmed
    • Mechanism by which a repressor transactivates these targets unresolved
  6. 2005 High

    Demonstrated that PAX4 and ARX jointly partition all three major fates, with double loss collapsing islets to delta cells.

    Evidence Arx/Pax4 double-knockout mice with immunohistology and transcript analysis

    PMID:15930104

    Open questions at the time
    • Did not identify the default delta-cell program operating in the absence of both factors
  7. 2006 High

    Defined the PAX4+ cell as a bipotent endocrine-duct progenitor and added activin A as a PAX4 inducer.

    Evidence Pax4-Cre lineage tracing with conditional Notch activation; promoter mutagenesis and E47/E12 siRNA

    PMID:16546275 PMID:17196797

    Open questions at the time
    • How Notch redirects PAX4+ cells at the transcriptional level not defined
    • activin study limited to cell-line context
  8. 2008 Medium

    Expanded PAX4 repressor targets to ghrelin and revealed extra-pancreatic expression and cAMP-mediated regulation in the pineal gland.

    Evidence Knockout lineage tracing for ghrelin cells; in situ hybridization with adrenergic/cAMP pharmacology

    PMID:18058910 PMID:18818287

    Open questions at the time
    • Direct PAX4 binding to ghrelin promoter not shown in this work
    • Functional role of pineal/retinal PAX4 unknown
  9. 2009 High

    Demonstrated PAX4 is sufficient to reprogram alpha cells to beta cells in vivo and regenerate functional beta-cell mass.

    Evidence Conditional cell-specific transgenic mice with lineage tracing and streptozotocin diabetes model

    PMID:19665969

    Open questions at the time
    • Whether human alpha cells are equally convertible not addressed
    • Durability and functional maturity of converted cells not fully resolved
  10. 2011 High

    Established PAX4 as a cytoprotective factor in mature beta cells through NF-kB target suppression and anti-apoptotic gene induction, and showed a disease mutant lacks this activity.

    Evidence Conditional transgenic mice (Pax4 vs Pax4R129W), streptozotocin and cytokine challenge, cytochrome C and IHC assays

    PMID:21521872

    Open questions at the time
    • Direct vs indirect mechanism of NF-kB target repression not defined
    • Mechanism of MafA repression not resolved
  11. 2015 High

    Showed PAX4 preserves ER homeostasis, defines an expandable proliferative beta-cell subpopulation, and can convert delta cells to beta-like cells.

    Evidence Transgenic/knock-in reporter mice, thapsigargin stress with EM and calcium imaging, siRNA, lineage tracing, diabetes models

    PMID:11263967 PMID:17260022 PMID:17717051 PMID:26503027 PMID:26813254 PMID:29025873

    Open questions at the time
    • Molecular basis for the ER-protective transcriptional program not mapped
    • What restricts PAX4 to a beta-cell subpopulation postnatally is unknown
  12. 2017 Medium

    Revealed an unexpected PAX4 role in muscle atrophy, inducing proteolytic machinery downstream of Trim32-mediated desmin disassembly.

    Evidence Denervation atrophy model with PAX4 and Trim32 shRNA knockdown and ubiquitin assays

    PMID:28096335

    Open questions at the time
    • Direct PAX4 target genes in muscle not genome-wide mapped
    • Single lab; relationship to islet PAX4 function unclear
  13. 2023 High

    Provided genome-wide PAX4 target identification in human beta cells and demonstrated functional requirement for insulin secretion and alpha-gene repression.

    Evidence siRNA in EndoC-βH1, CRISPR deletion in hiPSC-derived islets, CUT&RUN and RNA-sequencing; zebrafish ghrelin-binding studies

    PMID:36897579 PMID:37777536

    Open questions at the time
    • Co-regulators directing PAX4 to target loci not defined
    • Cross-species differences in target repertoire not fully reconciled
  14. 2025 High

    Defined human PAX4 loss-of-function disease mechanisms, showing complete loss causes transient neonatal diabetes and that some variants act by enhanced proteasomal degradation.

    Evidence Genome sequencing, CRISPR-edited hiPSC pancreatic endoderm, CUT&RUN; MIN6 expression with MG132 rescue

    PMID:15509590 PMID:17426099 PMID:22521316 PMID:25951767 PMID:40614820 PMID:41475885

    Open questions at the time
    • Why human PAX4 loss is transient while mouse loss is permanent not mechanistically explained
    • Which protein-quality-control machinery degrades unstable variants not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PAX4 enacts repression at the chromatin level — its co-repressor partners, the basis of its context-dependent activation of survival genes, and the species-specific essentiality difference — remains unresolved.
  • No co-repressor complex identified
  • Structural model of PAX4–DNA assembly not solved
  • Mechanism reconciling repressor identity with Bcl-xL/c-myc transactivation undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0003677 DNA binding 4
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
ARXHNF1ANEUROG3PDX1

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Homozygous inactivation of Pax4 in mice results in absence of mature insulin-producing beta cells and somatostatin-producing delta cells, with a concomitant increase in glucagon-producing alpha cells, establishing Pax4 as essential for beta and delta cell lineage differentiation from endocrine progenitors. Homologous recombination knockout mouse, immunohistochemistry Nature High 9121556
1999 PAX4 functions as a transcriptional repressor: it represses transcription through the glucagon and insulin promoters in alpha-cell lines, and repressor activity maps to multiple domains including the homeodomain and carboxyl terminus. A GAL4-PAX4 fusion also represses transcription through the GAL4 binding site, demonstrating intrinsic repressor activity independent of competition with PAX6. Transfection reporter assays, GAL4 fusion domain mapping, in vitro DNA binding Molecular and cellular biology High 10567552
1999 The Pax4 paired domain binds to optimal DNA sequences that overlap with Pax6 binding sites; the homeodomain preferentially dimerizes on DNA sequences with an inverted TAAT motif separated by 4-nucleotide spacing; the C-terminal region contains a transactivation domain with 2.5-fold lower activity than Pax6. PCR-based selection of optimal DNA binding sequences, gel shift assays, GAL4 reporter assays Biochemical and biophysical research communications Medium 10364449
1999 Pax4 contains both a portable repression domain and an E1A-responsive activation domain in its C-terminal region. The repression domain is cell-type independent, while the activation domain requires E1A or E1A-like activity. When the repression domain is linked to PDX-1's transactivation domain, it completely abolishes PDX-1 transactivation. GAL4-Pax4 chimera transfection assays, domain deletion mapping, E1A co-expression Molecular and cellular biology High 10567553
1999 Pax4 inhibits the human insulin promoter through the C2 box element (positions -253 to -244) and the islet amyloid polypeptide (IAPP) promoter through a sequence downstream of -138; inhibitory activity maps to two separate regions of the protein (amino acids 2-230 and 231-349). Reporter gene assays with promoter deletions, co-transfection in insulinoma cells FEBS letters Medium 10601637
2000 The human PAX4 promoter is controlled by pancreatic transcription factors HNF1alpha, HNF4alpha, PDX1, and a bHLH heterodimer binding to a 118-bp region ~1.9 kb upstream of the transcription start site. PAX4 itself binds at least two high-affinity sites within its own promoter to exert strong negative autoregulation. Transgenic reporter animals, deletion mapping, electrophoretic mobility shift assays, site-directed mutagenesis The Journal of biological chemistry High 10967107
2003 Arx and Pax4 have opposing actions in endocrine pancreas development: loss of Arx causes loss of alpha cells with increased beta and delta cells (opposite of Pax4 loss-of-function), and each mutant shows accumulation of the other's transcripts, indicating mutual transcriptional repression. Gene targeting knockout mice, immunohistology, multiplex RT-PCR Genes & development High 14561778
2003 Neurogenin3 and HNF1alpha cooperatively activate PAX4 transcription through synergy involving a physical interaction between the two factors and requiring the activation domains of both; the HNF1alpha and Ngn3 binding sites in the PAX4 promoter (~2 kb upstream) are critical for activity. Reporter gene assays, co-transfection, EMSA, exogenous Ngn3 expression in ductal cell lines and fibroblasts The Journal of biological chemistry High 12837760
2003 NSRF/NRSF binds to a neuron-restrictive silencer element (NRSE) in the Pax4 promoter that is highly conserved across evolution, forming a DNA-protein complex and conferring NRSF-dependent transcriptional repression of the Pax4 gene. EMSA (DNA-protein complex), reporter gene assays with NRSE mutations, NRSF co-transfection The Journal of biological chemistry Medium 12829700
2004 Pax4 activity is genetically required upstream of Pdx1, HB9, and insulin expression in beta-cell precursors; loss of Pax4 prevents initiation of beta-cell differentiation, and this occurs via genetic interaction with Nkx2.2. Pax4 knockout mouse analysis, immunohistochemistry for Pdx1/HB9/insulin in precursors, genetic epistasis with Nkx2.2 Developmental biology High 14729487
2004 Pax4 overexpression in rat and human islets causes beta-cell proliferation and upregulates Bcl-xL and c-myc; Pax4 transactivates the Bcl-xL and c-myc promoters, and Bcl-xL induction alters mitochondrial calcium levels and ATP production. Adenoviral overexpression, cell proliferation assays, luciferase reporter assays for Bcl-xL and c-myc promoters, mitochondrial calcium/ATP measurements The Journal of cell biology High 15596543
2005 Simultaneous loss of Arx and Pax4 results in near-exclusive generation of somatostatin-producing delta cells at the expense of alpha and beta cells, revealing that both Arx and Pax4 act as transcriptional repressors that control expression of one another to mediate endocrine fate allocation. Double knockout mice (Arx/Pax4), immunohistology, transcript analysis Development (Cambridge, England) High 15930104
2006 Notch signaling activation in Pax4+ endocrine progenitors inhibits their differentiation into alpha and beta cells and redirects them toward a duct fate, revealing that Pax4+ cells are bipotent endocrine-duct progenitors. Cre-loxP lineage tracing (Pax4-Cre), conditional Notch activation, immunohistochemistry Mechanisms of development High 17196797
2006 Activin A induces PAX4 expression through an E-box and HNF-1alpha binding sites ~1930 bp upstream of the transcription start site; activin A enhances the functional activity of E47/E12 bHLH proteins (without increasing their DNA binding), and siRNA knockdown of E47/E12 reduces activin A-induced PAX4 expression. Reporter gene assays with promoter deletions and mutations, siRNA knockdown, co-transfection in AR42J-B13 cells Biochimica et biophysica acta Medium 16546275
2007 PAX4 knockdown in rat insulinoma INS-1E cells reduces bcl-xl transcript levels and increases spontaneous apoptosis and cytokine-induced cell death, establishing Pax4 as a survival factor acting through upregulation of bcl-xl. Adenoviral shRNA knockdown, RT-PCR, apoptosis assays Oncogene Medium 17260022
2007 The paired domain of Pax4 functions as a novel protein transduction domain (PTD) enabling direct cellular uptake; transduced Pax4 protein inhibits Pax6-mediated transactivation and protects Min6 cells against TNF-alpha-induced apoptosis. Uptake is blocked by heparin. Protein transduction assays, heparin/cytochalasin D/amiloride blocking, reporter co-transfection, cell viability assays Endocrinology Medium 17717051
2008 Pax4 is expressed in rat pineal gland and retinal photoreceptors; in the pineal gland, nocturnal down-regulation of Pax4 mRNA is mediated by the adrenergic-cAMP signaling pathway (sympathetic norepinephrine release activates adrenergic receptors, triggering cAMP, which suppresses Pax4 expression). Northern blot, in situ hybridization, superior cervical ganglionectomy (sympathetic denervation), adrenergic agonist treatment in vivo and in vitro, cAMP mimic treatment Endocrinology Medium 18818287
2008 Pax4 is a transcriptional repressor of ghrelin in endocrine progenitors: Pax4-deficient mice have an overabundance of ghrelin-expressing cells in the pancreas and duodenum, and lineage tracing shows these cells arose directly from Pax4-deficient progenitors. Pax4 knockout analysis, immunohistochemistry, lineage-tracing Developmental dynamics Medium 18058910
2009 Conditional and ectopic expression of Pax4 forces endocrine precursor cells and mature alpha cells to adopt a beta cell destiny, causing glucagon deficiency that triggers compensatory Ngn3-dependent alpha cell neogenesis; the new alpha cells are then also converted by Pax4, creating a cycle that can restore functional beta cell mass and cure chemically induced diabetes. Conditional transgenic mice with cell-specific promoters, lineage tracing, streptozotocin diabetes model Cell High 19665969
2011 Conditional overexpression of Pax4 in beta cells protects against streptozotocin-induced hyperglycemia and cytokine-mediated apoptosis by suppressing selective NF-kB target genes (e.g., IL-1beta) and increasing Bcl-2, Cdk4, and c-myc; it also promotes dedifferentiation/proliferation of a Pdx1+ subpopulation through MafA repression. The diabetes-linked mutant Pax4R129W does not confer these protections. Conditional transgenic mice (Pax4 vs Pax4R129W), streptozotocin challenge, cytokine treatment of isolated islets, cytochrome C release assay, immunohistochemistry, quantitative RT-PCR Diabetes High 21521872
2012 In the intestine, Pax4 loss impairs differentiation of serotonin- and somatostatin-producing D cells while increasing GLP-1-producing L cells, concomitant with upregulation of Arx; Pax4 and Arx have antagonistic functions in D/L cell allocation downstream of Neurog3. Pax4 and Arx knockout mice analysis of intestine, histology, immunohistochemistry, lineage tracing PloS one Medium 22570716
2015 Ectopic expression of Pax4 in somatostatin-producing delta cells converts them into functional beta-like cells, inducing compensatory mechanisms including reactivation of endocrine developmental processes resulting in beta-like cell hyperplasia; these beta-like cells can partially reverse chemically induced diabetes. Transgenic mice with somatostatin-promoter-driven Pax4, lineage tracing, streptozotocin diabetes model, immunohistochemistry The Journal of cell biology High 29025873
2015 PAX4 overexpression preserves ER homeostasis in beta cells: PAX4-overexpressing islets are protected from thapsigargin-mediated ER-stress-induced apoptosis with preserved cytosolic calcium oscillations; PAX4 R129W mutant does not confer this protection. PAX4 knockdown sensitizes MIN6 cells to thapsigargin cell death. Conditional transgenic mice, thapsigargin treatment, electron microscopy, intracellular calcium measurements, siRNA knockdown, microarray profiling Diabetologia High 26813254
2015 PAX4 defines an expandable beta-cell subpopulation (~30% of islet cells) that preferentially proliferates during pregnancy and is more resistant to apoptosis under stress; lineage tracing demonstrates all islet cells derive from PAX4+ progenitors but GFP expression becomes restricted to a subpopulation postnatally. PAX4-GFP/Cre knock-in reporter mice, lineage tracing, immunohistochemistry, cell proliferation assays Scientific reports High 26503027
2017 During muscle atrophy induced by denervation, PAX4 induces expression of genes (including p97/VCP ATPase) required for myofibril breakdown in a second phase of atrophy; PAX4 downregulation attenuates myofibrillar protein loss. PAX4 acts downstream of desmin filament depolymerization by Trim32. Denervation atrophy model in mouse tibialis anterior, PAX4 shRNA knockdown, ubiquitin assays, Trim32 knockdown Proceedings of the National Academy of Sciences of the United States of America Medium 28096335
2018 SREBP1c directly targets PAX4 as a novel downstream gene to promote beta-cell proliferation and compensation under metabolic stress; SREBP1c-deficient mice show reduced PAX4 expression, glucose intolerance, and reduced beta-cell proliferation. SREBP1c knockout mice, islet transplantation, reporter assays, beta-cell proliferation assays Diabetes Medium 30352876
2001 A variant form of PAX4 (PAX4v) generated by alternative splicing lacking exon 7 in human insulinoma reverses wild-type PAX4-mediated repression of the insulin promoter in co-transfection assays, acting as a dominant negative. RT-PCR cloning, co-transfection reporter assays Biochemical and biophysical research communications Medium 11263967
2007 PAX4 R164W mutation impairs repressor activity of PAX4 on the insulin and glucagon promoters in vitro. Luciferase reporter assays in alpha-cell line with mutant PAX4 The Journal of clinical endocrinology and metabolism Medium 17426099
2004 PAX4 Arg133Trp variant shows decreased transcriptional repression of target gene promoters in alpha-TC1.6 cells; PAX4 Arg37Trp shows a more severe biochemical phenotype. Luciferase reporter assays in alpha-cell line Human molecular genetics Medium 15509590
2012 PAX4 R192H polymorphism reduces transcriptional repressor activities on human insulin and glucagon promoters while retaining normal nuclear localization. Luciferase reporter assays in beta-TC3 and alpha-TC-1.9 cells, Western blot for protein expression/compartmentalization Journal of diabetes and its complications Medium 22521316
2015 PAX4 IVS7-1G>A mutation causes aberrant mRNA splicing via cryptic splice site usage, resulting in a 3-nucleotide deletion (p.Q250del); Q250del protein has normal nuclear localization but significantly reduced repressor function on insulin and glucagon promoters and increases apoptosis under high-glucose conditions. Minigene splicing assay, Western blot, nuclear localization assay, luciferase reporter assays, apoptosis assay Acta diabetologica High 25951767
2023 In zebrafish, Pax4 binds to the ghrelin regulatory region and represses ghrelin transcription; deletion of Pax4 derepresses ghrelin expression, expanding epsilon cells that then transdifferentiate to beta cells and potentiate beta-cell regeneration after extreme beta-cell loss. Zebrafish Pax4 knockout, lineage tracing, NTR-mediated beta-cell ablation, overexpression of ghrelin/epsilon-cell expansion Development (Cambridge, England) Medium 36897579
2023 PAX4 knockdown in human EndoC-βH1 beta cells leads to impaired insulin secretion and reduced insulin content; PAX4 deletion in hiPSC-derived islets causes derepression of alpha cell gene expression; CUT&RUN-sequencing identifies direct PAX4 target genes involved in islet development and glucose-stimulated insulin secretion. siRNA knockdown in EndoC-βH1, CRISPR deletion in hiPSC-derived islets, CUT&RUN-sequencing, RNA-sequencing Nature communications High 37777536
2025 Complete homozygous loss of PAX4 in humans causes transient neonatal diabetes; PAX4 directly regulates genes involved in pancreatic islet development and glucose-stimulated insulin secretion as identified by CUT&RUN-sequencing in EndoC-βH1 cells; in contrast to mice, PAX4 is not absolutely essential for human beta-cell development (transient rather than permanent NDM). Genome sequencing, CRISPR-edited hiPSC pancreatic endoderm, CUT&RUN-sequencing, RNA-sequencing Molecular metabolism High 40614820
2025 Novel PAX4 variants (p.Gln28ArgfsTer6, p.Leu12Pro, p.Arg163Pro): the frameshift variant undergoes nonsense-mediated decay; the two missense variants retain nuclear localization but show markedly reduced protein levels due to enhanced proteasomal degradation (reversed by MG132 proteasome inhibitor treatment). Expression in MIN6 cells, Western blot, subcellular localization assay, proteasome inhibitor (MG132) rescue experiment BMJ open diabetes research & care Medium 41475885
2000 A beta-cell-specific enhancer in the Pax4 promoter resides in a region between -1858 and -1954 bp; DNase I footprinting and gel retardation assays show that nuclear proteins from beta cells interact with sequences containing CdxA/Nkx2 and GATA-1/-2 binding sites, both of which are necessary for enhancer activity. Promoter deletion reporter assays, DNase I footprinting, gel retardation/EMSA, site-directed mutagenesis Molecular and cellular endocrinology Medium 11162892
2011 In neonatal rat pancreas after streptozotocin treatment, Pax4 expression appears in alpha cells that also express Ngn3, consistent with alpha cells dedifferentiating into endocrine precursors capable of re-expressing Pax4. Double immunofluorescent staining for Ngn3, Pax4, and alpha-cell markers in neonatal rat pancreas World journal of gastroenterology Low 21734788

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 The Pax4 gene is essential for differentiation of insulin-producing beta cells in the mammalian pancreas. Nature 660 9121556
2003 Opposing actions of Arx and Pax4 in endocrine pancreas development. Genes & development 454 14561778
2009 The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells. Cell 444 19665969
2003 Expression of Pax4 in embryonic stem cells promotes differentiation of nestin-positive progenitor and insulin-producing cells. Proceedings of the National Academy of Sciences of the United States of America 324 12525695
2005 The simultaneous loss of Arx and Pax4 genes promotes a somatostatin-producing cell fate specification at the expense of the alpha- and beta-cell lineages in the mouse endocrine pancreas. Development (Cambridge, England) 175 15930104
1999 Paired-homeodomain transcription factor PAX4 acts as a transcriptional repressor in early pancreatic development. Molecular and cellular biology 151 10567552
2004 The diabetes-linked transcription factor PAX4 promotes {beta}-cell proliferation and survival in rat and human islets. The Journal of cell biology 135 15596543
2004 The concerted activities of Pax4 and Nkx2.2 are essential to initiate pancreatic beta-cell differentiation. Developmental biology 117 14729487
2007 PAX4 mutations in Thais with maturity onset diabetes of the young. The Journal of clinical endocrinology and metabolism 113 17426099
2003 Neurogenin3 and hepatic nuclear factor 1 cooperate in activating pancreatic expression of Pax4. The Journal of biological chemistry 95 12837760
2004 PAX4 gene variations predispose to ketosis-prone diabetes. Human molecular genetics 92 15509590
2001 A missense mutation of Pax4 gene (R121W) is associated with type 2 diabetes in Japanese. Diabetes 90 11723072
2012 The homeodomain-containing transcription factors Arx and Pax4 control enteroendocrine subtype specification in mice. PloS one 78 22570716
2004 The gene Pax4 is an essential regulator of pancreatic beta-cell development. Molecules and cells 73 15650323
2000 Autoregulation and maturity onset diabetes of the young transcription factors control the human PAX4 promoter. The Journal of biological chemistry 69 10967107
2022 Evaluation of Evidence for Pathogenicity Demonstrates That BLK, KLF11, and PAX4 Should Not Be Included in Diagnostic Testing for MODY. Diabetes 58 35108381
2005 Association of childhood type 1 diabetes mellitus with a variant of PAX4: possible link to beta cell regenerative capacity. Diabetologia 55 15834548
2017 Myofibril breakdown during atrophy is a delayed response requiring the transcription factor PAX4 and desmin depolymerization. Proceedings of the National Academy of Sciences of the United States of America 53 28096335
1999 Identification of a portable repression domain and an E1A-responsive activation domain in Pax4: a possible role of Pax4 as a transcriptional repressor in the pancreas. Molecular and cellular biology 53 10567553
2015 PAX4 Gene Transfer Induces α-to-β Cell Phenotypic Conversion and Confers Therapeutic Benefits for Diabetes Treatment. Molecular therapy : the journal of the American Society of Gene Therapy 50 26435408
2008 Developmental and diurnal dynamics of Pax4 expression in the mammalian pineal gland: nocturnal down-regulation is mediated by adrenergic-cyclic adenosine 3',5'-monophosphate signaling. Endocrinology 50 18818287
2015 Pax4 acts as a key player in pancreas development and plasticity. Seminars in cell & developmental biology 49 26319183
2006 Notch signaling reveals developmental plasticity of Pax4(+) pancreatic endocrine progenitors and shunts them to a duct fate. Mechanisms of development 49 17196797
2014 Transcriptional control of PAX4-regulated miR-144/451 modulates metastasis by suppressing ADAMs expression. Oncogene 46 25151965
2008 Ghrelin is a novel target of Pax4 in endocrine progenitors of the pancreas and duodenum. Developmental dynamics : an official publication of the American Association of Anatomists 46 18058910
2007 The diabetes-linked transcription factor Pax4 is expressed in human pancreatic islets and is activated by mitogens and GLP-1. Human molecular genetics 46 17989064
2008 A focus on the role of Pax4 in mature pancreatic islet beta-cell expansion and survival in health and disease. Journal of molecular endocrinology 45 18234907
2017 The Diabetes-Linked Transcription Factor PAX4: From Gene to Functional Consequences. Genes 40 28282933
2011 In vivo conditional Pax4 overexpression in mature islet β-cells prevents stress-induced hyperglycemia in mice. Diabetes 40 21521872
2018 Nonsynonymous Variants in PAX4 and GLP1R Are Associated With Type 2 Diabetes in an East Asian Population. Diabetes 39 29941447
2008 PAX4 enhances beta-cell differentiation of human embryonic stem cells. PloS one 38 18335054
2008 Developmental and daily expression of the Pax4 and Pax6 homeobox genes in the rat retina: localization of Pax4 in photoreceptor cells. Journal of neurochemistry 38 19012751
2016 PAX4 preserves endoplasmic reticulum integrity preventing beta cell degeneration in a mouse model of type 1 diabetes mellitus. Diabetologia 37 26813254
2011 A novel PAX4 mutation in a Japanese patient with maturity-onset diabetes of the young. The Tohoku journal of experimental medicine 37 21263211
2015 PAX4 Defines an Expandable β-Cell Subpopulation in the Adult Pancreatic Islet. Scientific reports 35 26503027
2007 The transcription factor PAX4 acts as a survival gene in INS-1E insulinoma cells. Oncogene 35 17260022
2002 Beta-cell dysfunction in late-onset diabetic subjects carrying homozygous mutation in transcription factors NeuroD1 and Pax4. Metabolism: clinical and experimental 35 12200761
2001 Pax4 regulatory elements mediate beta cell specific expression in the pancreas. Mechanisms of development 35 11118882
1999 Inhibitory effect of pax4 on the human insulin and islet amyloid polypeptide (IAPP) promoters. FEBS letters 35 10601637
2023 PAX4 loss of function increases diabetes risk by altering human pancreatic endocrine cell development. Nature communications 32 37777536
2006 Role of Pax4 in Pdx1-VP16-mediated liver-to-endocrine pancreas transdifferentiation. Laboratory investigation; a journal of technical methods and pathology 32 16732298
2017 Ectopic expression of Pax4 in pancreatic δ cells results in β-like cell neogenesis. The Journal of cell biology 31 29025873
1999 No evidence of linkage or diabetes-associated mutations in the transcription factors BETA2/NEUROD1 and PAX4 in Type II diabetes in France. Diabetologia 31 10230653
2011 Streptozotocin-induced expression of Ngn3 and Pax4 in neonatal rat pancreatic α-cells. World journal of gastroenterology 28 21734788
2015 Aberrant mRNA splicing of paired box 4 (PAX4) IVS7-1G>A mutation causing maturity-onset diabetes of the young, type 9. Acta diabetologica 26 25951767
2001 Expression of dominant negative form of PAX4 in human insulinoma. Biochemical and biophysical research communications 26 11263967
2003 Regulation of Pax4 paired homeodomain gene by neuron-restrictive silencer factor. The Journal of biological chemistry 25 12829700
2012 Defective PAX4 R192H transcriptional repressor activities associated with maturity onset diabetes of the young and early onset-age of type 2 diabetes. Journal of diabetes and its complications 23 22521316
2007 Enhancement of insulin-producing cell differentiation from embryonic stem cells using pax4-nucleofection method. World journal of gastroenterology 23 17461469
2007 Pax4 paired domain mediates direct protein transduction into mammalian cells. Endocrinology 23 17717051
1999 DNA binding and transactivating properties of the paired and homeobox protein Pax4. Biochemical and biophysical research communications 22 10364449
2013 Both PAX4 and MAFA are expressed in a substantial proportion of normal human pancreatic alpha cells and deregulated in patients with type 2 diabetes. PloS one 21 24013263
2006 The Arg121Trp variant in PAX4 gene is associated with beta-cell dysfunction in Japanese subjects with type 2 diabetes mellitus. Metabolism: clinical and experimental 21 16423628
2016 Exome-chip association analysis reveals an Asian-specific missense variant in PAX4 associated with type 2 diabetes in Chinese individuals. Diabetologia 20 27744525
2014 Evolution of the vertebrate Pax4/6 class of genes with focus on its novel member, the Pax10 gene. Genome biology and evolution 20 24951566
2014 Overexpression of PAX4 reduces glucagon expression in differentiating hESCs. Islets 20 25483960
2021 A nexus of miR-1271, PAX4 and ALK/RYK influences the cytoskeletal architectures in Alzheimer's Disease and Type 2 Diabetes. The Biochemical journal 19 34409981
2018 Generation and Phenotype Identification of PAX4 Gene Knockout Rabbit by CRISPR/Cas9 System. G3 (Bethesda, Md.) 19 29950431
2018 SREBP1c-PAX4 Axis Mediates Pancreatic β-Cell Compensatory Responses Upon Metabolic Stress. Diabetes 19 30352876
2017 PAX4 promotes PDX1-induced differentiation of mesenchymal stem cells into insulin-secreting cells. American journal of translational research 17 28386318
2016 PAX4 R192H and P321H polymorphisms in type 2 diabetes and their functional defects. Journal of human genetics 17 27334367
2008 PAX4 has the potential to function as a tumor suppressor in human melanoma. International journal of oncology 17 18949370
1998 Organisation of the human PAX4 gene and its exclusion as a candidate for the Wolcott-Rallison syndrome. Journal of medical genetics 17 9598721
2011 Co-orthology of Pax4 and Pax6 to the fly eyeless gene: molecular phylogenetic, comparative genomic, and embryological analyses. Evolution & development 15 23016906
2003 PAX4 mutation (R121W) as a prodiabetic variant in Okinawans. Biochemical and biophysical research communications 15 12604352
1994 Assignment of the human PAX4 gene to chromosome band 7q32 by fluorescence in situ hybridization. Cytogenetics and cell genetics 15 8287686
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
2000 Cloning of the mouse Pax4 gene promoter and identification of a pancreatic beta cell specific enhancer. Molecular and cellular endocrinology 14 11162892
2018 Therapeutic potential of pancreatic PAX4-regulated pathways in treating diabetes mellitus. Current opinion in pharmacology 13 30048825
2014 Association of PAX4 genetic variants with oral antidiabetic drugs efficacy in Chinese type 2 diabetes patients. The pharmacogenomics journal 13 24752311
2006 Aberrant DNA demethylation in promoter region and aberrant expression of mRNA of PAX4 gene in hematologic malignancies. Leukemia research 13 16701883
1998 Molecular cloning of rat Pax4: identification of four isoforms in rat insulinoma cells. Biochemical and biophysical research communications 13 9675102
2023 Pax4 in Health and Diabetes. International journal of molecular sciences 12 37175989
2022 C.487C>T mutation in PAX4 gene causes MODY9: A case report and literature review. Medicine 11 36595822
2005 Lack of association of PAX4 gene with type 1 diabetes in the Finnish and Hungarian populations. Diabetes 11 16123375
1998 Molecular cloning of mouse paired-box-containing gene (Pax)-4 from an islet beta cell line and deduced sequence of human Pax-4. Biochemical and biophysical research communications 11 9439631
2020 Identification of the First PAX4-MODY Family Reported in Brazil. Diabetes, metabolic syndrome and obesity : targets and therapy 10 32801813
2023 Pax4-Ghrelin mediates the conversion of pancreatic ε-cells to β-cells after extreme β-cell loss in zebrafish. Development (Cambridge, England) 9 36897579
2003 DNA sequence motifs conserved in endocrine promoters are essential for Pax4 expression. Developmental dynamics : an official publication of the American Association of Anatomists 9 14648838
2020 Pax4 Gene Delivery Improves Islet Transplantation Efficacy by Promoting β Cell Survival and α-to-β Cell Transdifferentiation. Cell transplantation 8 33086892
2008 The association of the PAX4 gene with type 1 diabetes in Han Chinese. Diabetes research and clinical practice 8 18617287
2022 Conversion of Gastrointestinal Somatostatin-Expressing D Cells Into Insulin-Producing Beta-Like Cells Upon Pax4 Misexpression. Frontiers in endocrinology 7 35573999
2021 Transcription factor PAX4 facilitates gastric cancer progression through interacting with miR-27b-3p/Grb2 axis. Aging 7 34162761
2018 PAX4 R192H is associated with younger onset of Type 2 diabetes in East Asians in Singapore. Journal of diabetes and its complications 6 30528630
2006 Activin A-induced expression of PAX4 in AR42J-B13 cells involves the increase in transactivation of E47/E12. Biochimica et biophysica acta 6 16546275
2020 Missense Variants in PAX4 Are Associated with Early-Onset Diabetes in Chinese. Diabetes therapy : research, treatment and education of diabetes and related disorders 5 33216280
2017 Improved insulin-secreting properties of pancreatic islet mesenchymal stem cells by constitutive expression of Pax4 and MafA. Turkish journal of biology = Turk biyoloji dergisi 5 30814862
2015 Pax4 Expression does not Transduce Pancreatic Alpha Cells to Beta Cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 5 26183751
2012 Generation of animals allowing the conditional inactivation of the Pax4 gene. Transgenic research 4 22717987
2009 No association of the IRS1 and PAX4 genes with type I diabetes. Genes and immunity 4 19956100
2000 IFN-gamma overexpression within the pancreas is not sufficient to rescue Pax4, Pax6, and Pdx-1 mutant mice from death. Pancreas 4 11075995
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
2022 Ethnic-Specific Type 2 Diabetes Risk Factor PAX4 R192H Is Associated with Attention-Specific Cognitive Impairment in Chinese with Type 2 Diabetes. Journal of Alzheimer's disease : JAD 2 35570489
2007 [Association between A1168C polymorphism in PAX4 gene and type 1 diabetes in Han Chinese]. Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae 2 17633464
2024 PAX4 gene delivery improves β-cell function in human islets of Type II diabetes. Regenerative medicine 1 39118533
2020 [Alternative Variants of Pax4 Human Transcription Factor: Comparative Transcriptional Activity]. Molekuliarnaia biologiia 1 33009794
2025 Complete loss of PAX4 causes transient neonatal diabetes in humans. Molecular metabolism 0 40614820
2025 Regulatory Mechanisms of CHD7 and PAX4 Gene Mutations on Proliferation and Apoptosis in Chondrocytes. Current molecular medicine 0 41088997
2025 dentification and characterization of novel PAX4 variants in patients with suspected MODY9. BMJ open diabetes research & care 0 41475885
2023 Production of Bioactive Human PAX4 Protein from E. coli. The protein journal 0 37552387

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