Affinage

NKX6-1

Homeobox protein Nkx-6.1 · UniProt P78426

Length
367 aa
Mass
37.8 kDa
Annotated
2026-04-29
78 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NKX6-1 is a homeodomain transcription factor that functions as a bifunctional regulator of cell fate specification in the pancreas and nervous system. Its homeodomain binds TAAT-containing sequences (consensus TTAATTAC), with a C-terminal acidic domain enhancing binding selectivity ~10-fold; the N-terminus mediates transcriptional repression, while the C-terminal acidic domain enables context-dependent activation, including positive autoregulation in beta cells (PMID:10799563, PMID:16101311, PMID:15056733). In the pancreas, NKX6-1 acts downstream of NKX2-2 in multipotent progenitors to specify beta-cell fate by directly repressing the alpha-cell determinant Arx (competing with Isl1), maintains beta-cell identity by activating Glut2, HNF1alpha, and insulin biosynthesis genes while suppressing delta-cell programs, and drives postnatal beta-cell proliferation through an Nr4a1/Nr4a3→E2F1/cyclin E→APC/UBE2C pathway and an AURKA→p53 degradation axis (PMID:11076772, PMID:23382704, PMID:24035389, PMID:24706823, PMID:26030060). In the developing nervous system, NKX6-1 specifies ventral progenitor identity to direct motor neuron and V2 interneuron fates, controls branchiomotor neuron migration through regulation of guidance receptors such as Ret and Unc5h3, and regulates astrocyte morphology and cholinergic synapse formation in a sex-specific manner via targets including Sema4A and Gabbr1 (PMID:10970877, PMID:14534138, PMID:39731735).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1999 High

    Establishing the DNA-binding specificity and transcriptional activity of NKX6-1 answered whether this homeodomain factor has sequence-selective DNA binding and what happens when it engages chromatin in different cell types.

    Evidence In vitro binding-site selection identified TTAATTG/A consensus; stable expression in alpha-cell line induced insulin gene expression

    PMID:10567713

    Open questions at the time
    • No genome-wide target identification
    • Mechanism of insulin induction in alpha cells undefined
  2. 2000 High

    Biochemical dissection of NKX6-1 revealed it is primarily a transcriptional repressor with an N-terminal repression domain and a C-terminal mobile interference domain that modulates DNA-binding selectivity, resolving how a single homeodomain protein achieves context-dependent regulation.

    Evidence In vitro DNA binding, Gal4 fusions, reporter assays, and deletion mutagenesis in fibroblasts and beta-cell lines

    PMID:10799563

    Open questions at the time
    • In vivo relevance of the interference domain not tested
    • No structural model of the C-terminal domain
  3. 2000 High

    Genetic studies established NKX6-1 as essential for both pancreatic beta-cell and ventral spinal cord neuron specification, placing it downstream of NKX2-2 in the pancreas and defining its domain of progenitor identity in the CNS.

    Evidence Nkx6.1 single and Nkx6.1/Nkx2.2 double KO mice (pancreas); Nkx6.1 targeted mutation with neuronal fate analysis (spinal cord)

    PMID:10970877 PMID:11076772

    Open questions at the time
    • Direct transcriptional targets in progenitors unknown
    • Mechanism of epistatic relationship with Nkx2.2 not molecularly defined
  4. 2004 High

    Discovery of NKX6-1 as a bifunctional factor—repressor at most targets but activator at its own promoter enhancer—explained how it maintains expression through positive autoregulation in beta cells.

    Evidence Reporter assays, EMSA, ChIP at -157 to -30 bp of Nkx6.1 promoter in betaTC3 cells; C-terminal activation domain mapping

    PMID:15056733

    Open questions at the time
    • Cofactors mediating the switch from repression to activation unidentified
    • Whether autoregulation operates in vivo not formally tested
  5. 2005 High

    Functional studies demonstrated that NKX6-1 suppresses glucagon expression and is required for glucose-stimulated insulin secretion, connecting its transcriptional activity to mature beta-cell function beyond developmental specification.

    Evidence RNAi knockdown reduced GSIS in INS-1 cells; overexpression suppressed glucagon in primary islets; quantitative binding selectivity of C-terminal domain measured

    PMID:15883383 PMID:16101311

    Open questions at the time
    • Direct glucagon promoter target mechanism not yet fully resolved
    • C-terminal selectivity not tested genome-wide
  6. 2007 High

    NKX6-1 was shown to inhibit glucagon transcription by competing with Pax6 at the G1 element and to require expression in multipotent Pdx1+ progenitors (not Ngn3+ precursors) for beta-cell specification, defining the precise developmental window and a direct antagonistic mechanism.

    Evidence ChIP/EMSA at glucagon G1 element; transgenic rescue in Nkx6.1 mutants with Pdx1- vs. Ngn3-driven constructs

    PMID:17263687 PMID:17537793

    Open questions at the time
    • Pax6-NKX6.1 interaction stoichiometry and dynamics in vivo unresolved
    • Chromatin context of competition not explored
  7. 2008 High

    NKX6-1 was identified as a direct driver of beta-cell proliferation through transcriptional activation of cell cycle genes (cyclins A2, B1, E), and its neuronal roles were extended to branchiomotor neuron migration (via Ret/Unc5h3) and motor pool identity.

    Evidence ChIP at cyclin promoters in primary rat islets with BrdU proliferation; Nkx6.1 KO analysis of hindbrain motor neuron migration and motor pool connectivity

    PMID:14534138 PMID:18215620 PMID:18347054

    Open questions at the time
    • How NKX6-1 switches from specifying fate to driving proliferation mechanistically unclear
    • Direct regulation of Ret/Unc5h3 not confirmed by ChIP
  8. 2010 High

    Direct activation of HNF1alpha by NKX6-1 linked this factor to a broader beta-cell transcriptional network, explaining part of how NKX6-1 maintains mature beta-cell gene expression.

    Evidence EMSA, ChIP, mutagenesis of NKX6-1 binding site in HNF1alpha promoter, gain/loss-of-function in beta-cell lines

    PMID:20106981

    Open questions at the time
    • HNF1alpha contribution to NKX6-1-dependent phenotypes not formally tested by epistasis
  9. 2013 High

    Two studies established that NKX6-1 is both necessary and sufficient for beta-cell identity: conditional adult deletion caused diabetes with delta-cell reprogramming, while NKX6-1 gain-of-function respecified non-beta precursors through direct Arx repression antagonistic to Isl1.

    Evidence Conditional KO in adult beta cells with genome-wide expression and secretion analysis; ChIP at Arx locus and genetic gain-of-function in endocrine precursors

    PMID:23382704 PMID:24035389

    Open questions at the time
    • Full set of direct repression targets maintaining identity vs. delta-cell fate not catalogued
    • Isl1-NKX6-1 competition mechanism at chromatin level unresolved
  10. 2014 High

    The proliferative pathway downstream of NKX6-1 was molecularly elaborated: NKX6-1 induces Nr4a1/Nr4a3 orphan nuclear receptors, which activate E2F1/cyclin E and the APC/UBE2C axis to degrade p21, and NKX6-1 is required for postnatal beta-cell mass expansion.

    Evidence Nr4a1 KO mice and adenoviral epistasis experiments; conditional Nkx6.1 KO in neonatal beta cells with BrdU and mass quantification

    PMID:24706823 PMID:25277396

    Open questions at the time
    • Whether Nr4a pathway operates in human beta-cell proliferation untested
    • Direct NKX6-1 binding at Nr4a1/Nr4a3 promoters not shown by ChIP
  11. 2015 High

    AURKA was identified as a direct NKX6-1 target that promotes beta-cell proliferation by phosphorylating and degrading p53, establishing a second parallel proliferative axis downstream of NKX6-1.

    Evidence ChIP at AURKA promoter, necessity/sufficiency tests with overexpression and shRNA, pharmacological inhibition

    PMID:26030060

    Open questions at the time
    • Relative contribution of Nr4a vs. AURKA axis to overall proliferation not quantified
    • p53 degradation mechanism details beyond phosphorylation unclear
  12. 2016 Medium

    NKX6-1 was found to regulate Notch1 expression through a specific intronic enhancer (CR2) in ventral neural progenitors, and c-Fos was identified as a mediator of NKX6-1-dependent Nr4a/VGF induction and beta-cell proliferation.

    Evidence ChIP at Notch1 CR2 enhancer with gain/loss-of-function in neural cells; c-Fos knockdown/overexpression epistasis in beta cells

    PMID:27164028 PMID:27924849

    Open questions at the time
    • Whether NKX6-1 directly activates c-Fos not established
    • CR2 enhancer activity not confirmed in mammalian neural progenitors in vivo beyond transgenic reporter
  13. 2024 Medium

    NKX6-1 was shown to regulate astrocyte morphology and cholinergic synapse formation in a sex-specific manner, with distinct DNA-binding and epigenomic profiles in males vs. females, identifying Sema4A and Gabbr1 as effectors.

    Evidence Conditional KO in ventral astrocytes, astrocyte morphology and synapse quantification, ChIP/ATAC-seq

    PMID:39731735

    Open questions at the time
    • Mechanism of sex-specific DNA binding not molecularly explained
    • Whether sex-specific effects extend beyond spinal cord astrocytes unknown
    • Sema4A/Gabbr1 not confirmed as direct targets by individual ChIP-qPCR

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of the C-terminal binding-interference/activation domain switch, the complete direct target repertoire in human beta cells and neurons, how NKX6-1 transitions from a fate-specification role to a proliferation/maintenance role, and the molecular basis of its sex-specific chromatin remodeling in astrocytes.
  • No crystal or cryo-EM structure of NKX6-1
  • Genome-wide direct target map in primary human beta cells lacking
  • Sex-specific cofactors or post-translational modifications unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0003677 DNA binding 5
Localization
GO:0005634 nucleus 5
Pathway
R-HSA-1266738 Developmental Biology 7 R-HSA-1640170 Cell Cycle 3 R-HSA-162582 Signal Transduction 2
Partners
BAF155ISL1NKX2-2NR4A1NR4A3PAX6PDX1RBBP7

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Nkx6.1 acts downstream of Nkx2.2 in the major pathway of beta-cell formation during the secondary transition; in Nkx6.1/Nkx2.2 double mutants, islet development is identical to Nkx2.2 single mutants, placing Nkx6.1 epistatic to Nkx2.2 in this pathway. Genetic epistasis using Nkx6.1 single knockout and Nkx6.1/Nkx2.2 double knockout mice with analysis of beta-cell precursors and beta-cell neogenesis Development High 11076772
2000 Nkx6.1 is required for somatic motor neuron and V2 interneuron fate specification in the ventral spinal cord; loss of Nkx6.1 causes a dorsal-to-ventral switch in progenitor identity and a compensatory expansion of V1 neurons. Targeted mutation in mice with analysis of neuronal progenitor domains and postmitotic neuron fates Genes & development High 10970877
2000 The Nkx6.1 homeodomain binds the consensus sequence TTAATTAC with high specificity; full-length Nkx6.1 has reduced DNA binding due to a C-terminal acidic domain that functions as a mobile binding interference domain; Nkx6.1 represses transcription through Nkx6.1 binding sites in fibroblasts and represses the insulin promoter through TAAT sequences in beta-cell lines; transcriptional repression maps to a discrete region in the amino terminus. In vitro DNA binding assays, Gal4 one-hybrid fusion studies, reporter gene analysis, deletion/mutagenesis Journal of Biological Chemistry High 10799563
2000 Nkx6.1 transcription is driven by a promoter with activity dependent on sequences at approximately -800 bp and the 5'-UTR; the homeodomain transcription factors PDX1 and Nkx2.2 bind to the -800 bp element; the 5'-UTR functions as an internal ribosomal entry site providing cell-type-specific translational regulation. Promoter deletion analysis, electrophoretic mobility shift assays (EMSA), dicistronic reporter assays Journal of Biological Chemistry High 10938085
1999 The Nkx6.1 homeodomain binds the DNA sequence TTAATTG/A identified by in vitro binding site selection; full-length Nkx6.1 fails to activate a reporter through this site despite robust in vitro binding; stable Nkx6.1 expression in alpha-cell-like MSL-G-AN cells induces endogenous insulin gene expression. In vitro binding site selection, reporter assays, stable transfection with Nkx6.1HD/VP16 fusion FEBS letters High 10567713
2004 Nkx6.1 is a bifunctional transcription factor: it represses target genes through A/T-rich sequences in most contexts but acts as a transcriptional activator at a beta-cell-specific enhancer element between -157 and -30 bp of its own promoter through a modular acidic C-terminal sequence, establishing positive autoregulatory feedback; Nkx6.1 binds this enhancer both in vitro and in vivo in betaTC3 cells. Reporter gene assays, EMSAs, chromatin immunoprecipitation (ChIP), deletion/mutagenesis Molecular Endocrinology High 15056733
2005 Nkx6.1 suppresses glucagon expression in beta-cell lines and primary islets, independent of Pdx1; RNAi-mediated knockdown of Nkx6.1 in glucose-responsive INS-1 class 3 cells causes a decrease in glucose-stimulated insulin secretion (GSIS) from 13.9-fold to 3.7-fold; overexpression of Nkx6.1 in glucose-unresponsive/glucagon-expressing class 1 cells suppresses glucagon expression. RNAi knockdown, overexpression with adenovirus, measurement of GSIS, mRNA quantification PNAS High 15883383
2005 The C-terminal domain of Nkx6.1 enhances sequence-selectivity of homeodomain DNA binding at TAAT sequences by ~10-fold (while reducing affinity only ~2-fold), and this selectivity is functionally preserved in mammalian cells; a stretch of conserved residues between amino acids 318-338 mediates this selectivity and can confer similar properties on the heterologous Pdx-1 homeodomain. Quantitative gel shift analysis, reporter gene analysis, deletional and mutational studies, circular dichroism spectroscopy Biochemistry High 16101311
2007 Nkx6.1 inhibits glucagon gene transcription by competing with Pax6 for binding to the G1 element of the glucagon promoter; Nkx6.1 interacts weakly with Pax6 in vitro and in vivo; ChIP confirms Nkx6.1 occupancy of the glucagon promoter in vivo. Transient transfection reporter assays, gel-shift/EMSA, site-directed mutagenesis, co-immunoprecipitation, chromatin immunoprecipitation Biochemical Journal High 17263687
2008 Nkx6.1 overexpression in primary rat islets induces beta-cell proliferation by upregulating cyclins A, B, and E, and several regulatory kinases; Nkx6.1 directly binds cyclin A2 and B1 gene promoters as shown by ChIP; cyclin E overexpression alone is sufficient to activate islet cell proliferation; Nkx6.1 overexpression enhances GSIS in rat islets and increases thymidine incorporation in human islets with retention of GSIS. Adenoviral overexpression, BrdU/thymidine incorporation, microarray, real-time PCR, immunoblot, chromatin immunoprecipitation (ChIP) Molecular and Cellular Biology High 18347054
2007 Nkx6.1 requires expression in multipotent Pdx1+ pancreatic progenitors (before Ngn3 activation) to specify beta-cell fate; expression of Nkx6.2 in Pdx1+ progenitors rescues beta-cell formation in Nkx6.1 mutant mice equivalently to Nkx6.1, demonstrating that Nkx6.1 and Nkx6.2 have equivalent biochemical activities and that their distinct developmental roles arise from divergent expression domains. Transgenic rescue experiments in Nkx6.1 mutant mice with Pdx1- or Ngn3-promoter-driven transgenes Development High 17537793
2008 Nkx6.1 is required for migration and axon pathfinding of cranial branchio-motoneurons in the hindbrain; in Nkx6.1 mutants, facial branchio-motoneurons show ectopic expression of cell surface receptors Ret and Unc5h3, suggesting a cell-autonomous role for Nkx6.1 in controlling migration through regulation of guidance receptors. Analysis of Nkx6.1-deficient mouse embryos, immunohistochemistry for Ret and Unc5h3 expression Development High 14534138
2008 Nkx6.1 controls the identity and fate of red nucleus neurons in the ventral midbrain; Nkx6-1 is also expressed in postmitotic oculomotor/trochlear neurons and controls their migration and axon outgrowth by regulating axon guidance/neuronal migration molecules. Mouse genetics (Nkx6-1 KO), in situ hybridization, immunohistochemistry Development High 19592574
2008 Nkx6.1 motor pool expression status defines early transcriptional identity of motor pools prior to axon branching, and regulates muscle nerve formation and specific muscle innervation patterns. Mouse genetics, analysis of motor pool identity and nerve-muscle connectivity Neuron High 18215620
2013 Conditional inactivation of Nkx6.1 in adult mouse beta-cells causes rapid-onset diabetes and hypoinsulinemia; Nkx6.1 controls insulin biosynthesis, insulin secretion, and beta-cell proliferation; loss of Nkx6.1 causes beta-cells to acquire molecular characteristics of delta cells, revealing a molecular link between impaired beta-cell function and loss of cell identity. Conditional knockout in adult mice, genome-wide analysis of regulated genes, functional secretion assays Cell Reports High 24035389
2013 Nkx6.1 is both necessary and sufficient to specify insulin-producing beta cells from endocrine precursors; heritable Nkx6.1 expression in endocrine precursors respecifies non-beta precursors towards beta cell lineage; Nkx6.1 directly binds and represses the alpha-cell determinant Arx; Nkx6.1 and the Arx activator Isl1 regulate Arx transcription antagonistically, establishing competition as a mechanism for alpha vs. beta cell identity determination. Conditional KO and gain-of-function mouse genetics, ChIP for Arx binding, reporter assays PLoS Genetics High 23382704
2014 Nkx6.1 induces expression of orphan nuclear receptors Nr4a1 and Nr4a3, which are both necessary and sufficient for Nkx6.1-mediated beta-cell proliferation; Nr4a receptors increase E2F1 and cyclin E1 expression and induce components of the anaphase-promoting complex including UBE2C, leading to degradation of p21. Adenoviral overexpression and knockdown, global Nr4a1 knockout mice, cell cycle marker analysis PNAS High 24706823
2014 Nkx6.1 is required for postnatal beta-cell mass expansion; genetic inactivation in newly formed beta-cells causes drastic decrease in early postnatal beta-cell proliferation and reduced beta-cell mass; Nkx6.1 regulates expression of beta-cell maturation markers and nutrient sensors Glut2 and Glp1r. Conditional knockout in neonatal mice, BrdU proliferation assay, beta-cell mass measurement, gene expression analysis Diabetes High 25277396
2010 NKX6.1 binds to a cis-regulatory element in the HNF1alpha promoter and activates HNF1alpha gene expression in beta-cells; site-directed mutagenesis of the NKX6.1 core-binding sequence eliminates NKX6.1-mediated activation; overexpression or siRNA knockdown of Nkx6.1 correspondingly increases or decreases HNF1alpha expression. EMSA, ChIP, reporter assays, site-directed mutagenesis, siRNA knockdown, overexpression Journal of Biological Chemistry High 20106981
2015 Nkx6.1 localizes to the promoter of AURKA (Aurora Kinase A) and induces its expression; adenoviral overexpression of AURKA is sufficient to induce beta-cell proliferation; AURKA is necessary for Nkx6.1-mediated beta-cell proliferation; AURKA induces phosphorylation and degradation of p53 to permit cell cycle progression. ChIP, adenoviral overexpression, shRNA knockdown, pharmacological inhibition, BrdU incorporation, histone H3 phosphorylation assay Islets High 26030060
2016 Nkx6.1-mediated upregulation of Nr4a1, Nr4a3, and VGF depends on c-Fos expression; c-Fos overexpression activates Nkx6.1-responsive genes and increases beta-cell proliferation, insulin secretion, and survival; c-Fos knockdown impedes Nkx6.1-mediated beta-cell proliferation and insulin secretion. Adenoviral overexpression and shRNA knockdown of c-Fos, gene expression analysis, BrdU proliferation, GSIS assay FEBS Letters Medium 27164028
2015 NKX6.1 suppresses tumor metastasis and EMT by directly enhancing E-cadherin mRNA expression through recruitment of BAF155 coactivator and repressing vimentin and N-cadherin by recruiting RBBP7 corepressor. Co-immunoprecipitation, reporter assays, in vitro and in vivo metastasis assays, loss-of-function Oncogene Medium 26257059
2016 NKX6.1 directly binds the proximal region of the IL6 promoter in basal-like breast cancer cells and upregulates IL-6 expression, which promotes cancer cell growth; NKX6.1 depletion reduces IL6 promoter activity and cell growth. Pull-down assay, reporter assay, loss-of-function knockdown, rescue with exogenous IL-6, xenograft tumor formation Experimental Cell Research Medium 27032575
2016 Nkx6.1 regulates Notch1 expression in ventral neural stem/progenitor cells of the developing spinal cord by interacting with a 139 bp enhancer sequence (CR2) in the second intron of the Notch1 locus; knockdown or overexpression of Nkx6.1 leads to corresponding down- or up-regulation of Notch1 expression. Luciferase reporter assays, ChIP, shRNA knockdown, overexpression, CR2-GFP transgenic mouse analysis Scientific Reports Medium 27924849
2014 Control of astrocyte progenitor specification, migration, and maturation in the ventral spinal cord requires Nkx6.1; conventional Nkx6.1 KO disrupts initial specification of astrocyte progenitors and migration/differentiation; conditional KO reveals delayed differentiation and disorganized arrangement of fibrous astrocytes. Conventional and conditional Nkx6.1 knockout mouse analysis, immunohistochemistry PloS One Medium 25285789
2020 The lncRNA ROIT binds DNA methyltransferase DNMT3a and causes its degradation through the ubiquitin-proteasome pathway, thereby blocking methylation of the Nkx6.1 promoter and maintaining Nkx6.1 expression for insulin transcription; reduced ROIT in obese mice leads to increased Nkx6.1 promoter methylation and beta-cell dysfunction. RNA pull-down, RNA immunoprecipitation, co-immunoprecipitation, bisulfite sequencing, siRNA knockdown/overexpression Diabetologia Medium 32008054
2010 NKX6.1 activates immature pancreatic markers NGN-3 and ISL-1 but not pancreatic hormone genes in human liver cells; NKX6.1 together with ectopic PDX-1 substantially and specifically promotes insulin expression and glucose-regulated insulin secretion to a greater extent than PDX-1 alone; NKX6.1 represses PDX-1-induced proglucagon expression. Adenoviral overexpression of NKX6.1 and/or PDX-1 in human liver cells, gene expression analysis, insulin secretion assay Cellular Reprogramming Medium 21108535
2003 Adult postnatal spinal cord ependymal cells are derived from Nkx6.1+ ventral neural progenitor cells; Nkx6.1 expression in ependymal cells is maintained and regulated by Shh signaling from the floor plate. Immunohistochemistry and in situ hybridization tracking of Nkx6.1+ progenitor lineage in chick and mouse Journal of Comparative Neurology Medium 12528188
2024 Nkx6.1 is specifically expressed in ventral astrocytes of the spinal cord; its deletion causes sex-specific effects on astrocyte morphology with enhanced complexity in males (accompanied by increased motor function and cholinergic synapses) and reduced complexity in females; Nkx6.1 exhibits sex-specific DNA-binding properties and epigenomic remodeling, with Semaphorin 4A (Sema4A) and Gabbr1 identified as targets regulating astrocyte morphology and cholinergic synapse formation. Conditional knockout, astrocyte morphology analysis, motor function assays, synapse quantification, ChIP/ATAC-seq Cell Reports Medium 39731735
2021 Lentivirus-mediated Nkx6.1 expression in adult injured mouse spinal cord promotes proliferation of endogenous neural stem/progenitor cells, increases interneurons, reduces reactive astrocytes and glial scar, and represses neuroinflammation; transcriptomic analysis shows Nkx6.1 upregulates Notch signaling genes and downregulates neuroinflammation/reactive astrocyte pathways. Lentiviral overexpression in spinal cord injury mouse model, immunohistochemistry, RNA sequencing Experimental Neurology Medium 34343529
2019 Bioinformatics analysis identified NKX6-1 binding motifs in promoters of ~78% of high-priority candidate genes deregulated in Fgfr2-deficient lenses; biochemical reporter assays demonstrated that NKX6-1 directly activates RASGRP1 expression, suggesting a regulatory module in which NKX6-1 activates Rasgrp1 to restore ERK/AKT balance. Transcriptomic analysis, luciferase reporter assays Human Genetics Low 31691004

Source papers

Stage 0 corpus · 78 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Homeobox gene Nkx6.1 lies downstream of Nkx2.2 in the major pathway of beta-cell formation in the pancreas. Development (Cambridge, England) 426 11076772
2013 Nkx6.1 is essential for maintaining the functional state of pancreatic beta cells. Cell reports 268 24035389
2015 Efficient generation of NKX6-1+ pancreatic progenitors from multiple human pluripotent stem cell lines. Stem cell reports 231 25843049
2000 Ventral neural patterning by Nkx homeobox genes: Nkx6.1 controls somatic motor neuron and ventral interneuron fates. Genes & development 224 10970877
2013 Enrichment of human embryonic stem cell-derived NKX6.1-expressing pancreatic progenitor cells accelerates the maturation of insulin-secreting cells in vivo. Stem cells (Dayton, Ohio) 212 23897760
2013 Nkx6.1 controls a gene regulatory network required for establishing and maintaining pancreatic Beta cell identity. PLoS genetics 180 23382704
2005 The Nkx6.1 homeodomain transcription factor suppresses glucagon expression and regulates glucose-stimulated insulin secretion in islet beta cells. Proceedings of the National Academy of Sciences of the United States of America 134 15883383
2020 NKX6.1 transcription factor: a crucial regulator of pancreatic β cell development, identity, and proliferation. Stem cell research & therapy 100 33121533
2007 The transcription factors Nkx6.1 and Nkx6.2 possess equivalent activities in promoting beta-cell fate specification in Pdx1+ pancreatic progenitor cells. Development (Cambridge, England) 95 17537793
2008 Stimulation of human and rat islet beta-cell proliferation with retention of function by the homeodomain transcription factor Nkx6.1. Molecular and cellular biology 91 18347054
2014 Nkx6.1 regulates islet β-cell proliferation via Nr4a1 and Nr4a3 nuclear receptors. Proceedings of the National Academy of Sciences of the United States of America 84 24706823
2008 Early motor neuron pool identity and muscle nerve trajectory defined by postmitotic restrictions in Nkx6.1 activity. Neuron 80 18215620
2003 Molecular mapping of the origin of postnatal spinal cord ependymal cells: evidence that adult ependymal cells are derived from Nkx6.1+ ventral neural progenitor cells. The Journal of comparative neurology 67 12528188
2018 Enhanced differentiation of human pluripotent stem cells into pancreatic progenitors co-expressing PDX1 and NKX6.1. Stem cell research & therapy 65 29361979
2009 Nkx6-1 controls the identity and fate of red nucleus and oculomotor neurons in the mouse midbrain. Development (Cambridge, England) 65 19592574
2007 Peroxisome proliferator-activated receptor-gamma regulates expression of PDX-1 and NKX6.1 in INS-1 cells. Diabetes 61 17192469
2003 Nkx6.1 controls migration and axon pathfinding of cranial branchio-motoneurons. Development (Cambridge, England) 58 14534138
2000 Transcriptional and translational regulation of beta-cell differentiation factor Nkx6.1. The Journal of biological chemistry 56 10938085
2000 Beta-cell differentiation factor Nkx6.1 contains distinct DNA binding interference and transcriptional repression domains. The Journal of biological chemistry 53 10799563
2014 High methylation rate of LMX1A, NKX6-1, PAX1, PTPRR, SOX1, and ZNF582 genes in cervical adenocarcinoma. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 52 24407576
2008 Generation and characterization of Ptf1a antiserum and localization of Ptf1a in relation to Nkx6.1 and Pdx1 during the earliest stages of mouse pancreas development. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 51 18347078
2015 Progenitor potential of nkx6.1-expressing cells throughout zebrafish life and during beta cell regeneration. BMC biology 46 26329351
2002 Caenorhabditis elegans cog-1 locus encodes GTX/Nkx6.1 homeodomain proteins and regulates multiple aspects of reproductive system development. Developmental biology 46 12482710
2004 The transcriptional repressor Nkx6.1 also functions as a deoxyribonucleic acid context-dependent transcriptional activator during pancreatic beta-cell differentiation: evidence for feedback activation of the nkx6.1 gene by Nkx6.1. Molecular endocrinology (Baltimore, Md.) 45 15056733
2010 NKX6.1 promotes PDX-1-induced liver to pancreatic β-cells reprogramming. Cellular reprogramming 41 21108535
2016 Directed differentiation of human iPSC into insulin producing cells is improved by induced expression of PDX1 and NKX6.1 factors in IPC progenitors. Journal of translational medicine 38 27998294
2020 Obesity-induced reduced expression of the lncRNA ROIT impairs insulin transcription by downregulation of Nkx6.1 methylation. Diabetologia 36 32008054
2020 Controlled clustering enhances PDX1 and NKX6.1 expression in pancreatic endoderm cells derived from pluripotent stem cells. Scientific reports 34 31988329
2015 NKX6.1 functions as a metastatic suppressor through epigenetic regulation of the epithelial-mesenchymal transition. Oncogene 34 26257059
2010 Nkx6.1 and nkx6.2 regulate alpha- and beta-cell formation in zebrafish by acting on pancreatic endocrine progenitor cells. Developmental biology 33 20122912
1999 Cloning and DNA-binding properties of the rat pancreatic beta-cell-specific factor Nkx6.1. FEBS letters 33 10567713
2014 Postnatal β-cell proliferation and mass expansion is dependent on the transcription factor Nkx6.1. Diabetes 31 25277396
2016 Nkx6.1-mediated insulin secretion and β-cell proliferation is dependent on upregulation of c-Fos. FEBS letters 30 27164028
2007 The beta-cell specific transcription factor Nkx6.1 inhibits glucagon gene transcription by interfering with Pax6. The Biochemical journal 29 17263687
2018 Differentiation of human pluripotent stem cells into two distinct NKX6.1 populations of pancreatic progenitors. Stem cell research & therapy 27 29615106
2015 Aurora Kinase A is critical for the Nkx6.1 mediated β-cell proliferation pathway. Islets 23 26030060
2014 Silymarin induces expression of pancreatic Nkx6.1 transcription factor and β-cells neogenesis in a pancreatectomy model. Molecules (Basel, Switzerland) 23 24739928
2011 Transgenic overexpression of the transcription factor Nkx6.1 in β-cells of mice does not increase β-cell proliferation, β-cell mass, or improve glucose clearance. Molecular endocrinology (Baltimore, Md.) 23 21964593
2006 Generation and characterization of monoclonal antibodies against the transcription factor Nkx6.1. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 21 16401696
2020 PDX1- /NKX6.1+ progenitors derived from human pluripotent stem cells as a novel source of insulin-secreting cells. Diabetes/metabolism research and reviews 20 32857429
2018 NKX6.1 induced pluripotent stem cell reporter lines for isolation and analysis of functionally relevant neuronal and pancreas populations. Stem cell research 20 29734117
2016 Transcriptional Regulation of Notch1 Expression by Nkx6.1 in Neural Stem/Progenitor Cells during Ventral Spinal Cord Development. Scientific reports 20 27924849
2010 Dynamic expression patterns of Nkx6.1 and Nkx6.2 in the developing mes-diencephalic basal plate. Developmental dynamics : an official publication of the American Association of Anatomists 20 20549744
2001 Chicken Nkx6.1 expression at advanced stages of development identifies distinct brain nuclei derived from the basal plate. Mechanisms of development 20 11287211
2020 NKX6.1 Represses Tumorigenesis, Metastasis, and Chemoresistance in Colorectal Cancer. International journal of molecular sciences 19 32707737
2014 Extra-nuclear activity of INSM1 transcription factor enhances insulin receptor signaling pathway and Nkx6.1 expression through RACK1 interaction. Cellular signalling 17 24407176
2010 Nkx6 genes pattern the frog neural plate and Nkx6.1 is necessary for motoneuron axon projection. Developmental biology 17 21035438
2005 The C-terminal domain of the beta cell homeodomain factor Nkx6.1 enhances sequence-selective DNA binding at the insulin promoter. Biochemistry 16 16101311
2019 High-throughput transcriptome analysis reveals that the loss of Pten activates a novel NKX6-1/RASGRP1 regulatory module to rescue microphthalmia caused by Fgfr2-deficient lenses. Human genetics 15 31691004
2014 Control of astrocyte progenitor specification, migration and maturation by Nkx6.1 homeodomain transcription factor. PloS one 15 25285789
1997 Isolation, characterization, and chromosomal mapping of the human Nkx6.1 gene (NKX6A), a new pancreatic islet homeobox gene. Genomics 15 9119408
2018 NKX6.1 hypermethylation predicts the outcome of stage II colorectal cancer patients undergoing chemotherapy. Genes, chromosomes & cancer 14 29363224
2021 Nkx6.1 enhances neural stem cell activation and attenuates glial scar formation and neuroinflammation in the adult injured spinal cord. Experimental neurology 13 34343529
2018 Immunohistochemical analysis of OTP and NKX6.1 in neuroendocrine tumors of the lung and pancreas. Diagnostic cytopathology 13 30284410
2021 NKX6-1 mediates cancer stem-like properties and regulates sonic hedgehog signaling in leiomyosarcoma. Journal of biomedical science 12 33906647
2017 Nkx6.1 decline accompanies mitochondrial DNA reduction but subtle nucleoid size decrease in pancreatic islet β-cells of diabetic Goto Kakizaki rats. Scientific reports 12 29142323
2019 Zebrafish prdm12b acts independently of nkx6.1 repression to promote eng1b expression in the neural tube p1 domain. Neural development 10 30813944
2013 Reprogramming of enteroendocrine K cells to pancreatic β-cells through the combined expression of Nkx6.1 and Neurogenin3, and reaggregation in suspension culture. Biochemical and biophysical research communications 10 24365150
2010 Distinct regulation of hepatic nuclear factor 1alpha by NKX6.1 in pancreatic beta cells. The Journal of biological chemistry 10 20106981
2021 Increased NKX6.1 expression and decreased ARX expression in alpha cells accompany reduced beta-cell volume in human subjects. Scientific reports 8 34493754
2011 Isolation of mineralizing Nestin+ Nkx6.1+ vascular muscular cells from the adult human spinal cord. BMC neuroscience 8 21985235
2024 Deletion of RFX6 impairs iPSC-derived islet organoid development and survival, with no impact on PDX1+/NKX6.1+ progenitors. Diabetologia 7 39080045
2018 Methylation in the promoter regions of WT1, NKX6-1 and DBC1 genes in cervical cancer tissues of Uygur women in Xinjiang. Genetics and molecular biology 7 29658966
2017 Efficient Differentiation of Pluripotent Stem Cells to NKX6-1+ Pancreatic Progenitors. Journal of visualized experiments : JoVE 7 28362406
2016 A homeobox protein, NKX6.1, up-regulates interleukin-6 expression for cell growth in basal-like breast cancer cells. Experimental cell research 7 27032575
2023 Deficiency of transcription factor Nkx6.1 does not prevent insulin secretion in INS-1E cells. Scientific reports 6 36639413
2020 MiR-190b impedes pancreatic β cell proliferation and insulin secretion by targeting NKX6-1 and may associate to gestational diabetes mellitus. Journal of receptor and signal transduction research 6 32862769
2020 Netrin-1/DCC Signaling Differentially Regulates the Migration of Pax7, Nkx6.1, Irx2, Otp, and Otx2 Cell Populations in the Developing Interpeduncular Nucleus. Frontiers in cell and developmental biology 6 33195252
2013 Xenopus Nkx6.1 and Nkx6.2 are required for mid-hindbrain boundary development. Development genes and evolution 6 23423436
2008 Specificity of four monoclonal anti-NKx6-1 antibodies. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 6 18212389
2022 Highly Efficient Differentiation of Human Pluripotent Stem Cells into Pancreatic Progenitors Co-expressing PDX1 and NKX6.1. Methods in molecular biology (Clifton, N.J.) 4 33190184
2021 Increased frequency of β cells with abnormal NKX6.1 expression in type 2 diabetes but not in subjects with higher risk for type 2 diabetes. BMC endocrine disorders 4 33711989
2024 Sex-specific astrocyte regulation of spinal motor circuits by Nkx6.1. Cell reports 3 39731735
2022 NKX6-1 Is a Less Sensitive But Specific Biomarker of Chromophobe Renal Cell Carcinoma. The American journal of surgical pathology 2 35256556
2024 MIR124-3 and NKX6-1 hypermethylation profiles accurately predict metachronous gastric lesions in a Caucasian population. Clinical epigenetics 1 39169394
2021 Generation of a Novel Nkx6-1 Venus Fusion Reporter Mouse Line. International journal of molecular sciences 1 33810480
2026 NKX6.1 mRNA copy number is an actionable biomarker associated with islet function and clinical outcomes after islet transplantation. Science translational medicine 0 41880516
2022 Micro-RNA-124-5p promotes insulin producing cell differentiation through regulating transcriptional factor NKX6.1. Biochemistry and biophysics reports 0 35592615