Affinage

SIX2

Homeobox protein SIX2 · UniProt Q9NPC8

Length
291 aa
Mass
32.3 kDa
Annotated
2026-04-28
84 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SIX2 is a homeodomain transcription factor that maintains multipotent progenitor populations in an undifferentiated, self-renewing state, most extensively characterized in nephron progenitors of the developing kidney but also operative in cardiac, craniofacial, and pancreatic β-cell contexts. In nephron progenitors, SIX2 opposes Wnt9b/β-catenin–directed epithelial differentiation by co-occupying cis-regulatory modules at target loci (Wnt4, Fgf8) together with Lef/Tcf factors and by recruiting the Brg1-SWI/SNF chromatin-remodeling complex to progenitor-specific enhancers (PMID:22902740, PMID:34716243). SIX2 possesses a C-terminal transcriptional activation domain and directly activates promoters of Gdnf, Smurf1, Sox2, and other targets through sequence-specific DNA binding, and its activity is controlled post-translationally by Eya1-mediated dephosphorylation facilitating nuclear translocation and by TRIM21-catalyzed K48-linked ubiquitination targeting it for proteasomal degradation (PMID:15327782, PMID:25458011, PMID:40954199). In cancer contexts, SIX2 reactivates stem-cell programs—including Sox2, E-cadherin repression via Zeb2, and PI3K/Akt signaling—to promote metastasis and therapy resistance (PMID:25348955, PMID:30606720).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2004 Medium

    Establishing that SIX2 is a sequence-specific transcriptional activator resolved the basic molecular activity of the protein: it binds homeodomain-like elements in the Gdnf promoter and its own promoter, and carries a C-terminal activation domain.

    Evidence Promoter-reporter assays, binding-site identification, and transgenic LacZ reporter mice

    PMID:15327782

    Open questions at the time
    • No genome-wide binding map; target specificity versus other SIX family members unknown
    • Activation domain boundaries not precisely mapped
  2. 2006 High

    Demonstrating that Six2 loss causes premature epithelial differentiation and progenitor depletion, while gain-of-function blocks differentiation, established SIX2 as the key maintenance factor for nephron progenitors opposing Wnt-directed nephrogenesis.

    Evidence Loss-of-function mouse genetics and gain-of-function organ culture

    PMID:17036046

    Open questions at the time
    • Molecular targets through which SIX2 opposes Wnt signaling not yet identified
    • Whether SIX2 acts cell-autonomously not formally demonstrated
  3. 2008 High

    Lineage tracing and clonal analysis proved that SIX2-expressing cells are a multipotent, self-renewing nephron progenitor population and that SIX2 functions cell-autonomously, resolving the cellular identity of the progenitor pool.

    Evidence Six2-Cre genetic lineage tracing, clonal analysis, conditional knockout, organ culture

    PMID:18682239

    Open questions at the time
    • Mechanism of self-renewal versus differentiation switch at the chromatin level unresolved
    • Relationship to other progenitor markers (Osr1, Sall1) not delineated
  4. 2008 Medium

    Placing Six2 as a direct downstream target of Hoxa2 during branchial arch development revealed that SIX2 operates in a broader Hox-regulated developmental hierarchy beyond the kidney.

    Evidence Genetic epistasis and ectopic expression in Hoxa2-mutant mice

    PMID:18321982

    Open questions at the time
    • Direct Hox binding sites in Six2 regulatory region not mapped
    • Six2 targets in branchial arch mesenchyme unknown
  5. 2009 Medium

    Dissecting a single Six2 enhancer that is activated by Hox11 in kidney and repressed by Hoxa2 in face showed that tissue-specific Six2 expression is governed by flanking Hox protein domains rather than homeodomain DNA-binding specificity.

    Evidence In vivo enhancer analysis with domain-swap mutagenesis in transgenic reporter mice

    PMID:19716816

    Open questions at the time
    • Cofactors mediating activation versus repression at the shared enhancer not identified
    • Whether this enhancer is sufficient for all Six2 kidney expression not tested
  6. 2010 Medium

    Loss-of-function and gain-of-function studies in the cranial base demonstrated that SIX2 controls chondrocyte proliferation and opposes terminal differentiation, extending its progenitor-maintenance role to skeletal development.

    Evidence Six2-null and gain-of-function mouse genetics with histological chondrocyte analysis

    PMID:20515681

    Open questions at the time
    • Direct transcriptional targets in chondrocytes not identified
    • Relationship to Wnt or other signaling pathways in this context unknown
  7. 2012 High

    ChIP and co-occupancy analysis showed that SIX2 and β-catenin bind shared cis-regulatory elements at Wnt4/Fgf8 through Lef/Tcf factors, revealing that progenitor self-renewal and Wnt-directed differentiation operate through the same gene regulatory network with opposing transcriptional outcomes.

    Evidence ChIP, transcriptional profiling, Lef/Tcf binding site mutagenesis in vivo

    PMID:22902740

    Open questions at the time
    • How β-catenin entry into the SIX2–Lef/Tcf complex switches output from maintenance to differentiation is mechanistically unclear
    • Genome-wide extent of SIX2–β-catenin co-occupancy not fully mapped
  8. 2014 High

    Identifying the Eya1–Six2–Myc interaction established a phosphatase-dependent signaling axis within the progenitor nucleus: Eya1 uses its threonine phosphatase activity on Myc, and Six2 mediates Eya1 nuclear import, linking post-translational modification to progenitor self-renewal.

    Evidence Co-immunoprecipitation, conditional knockout, phosphatase activity assay, nuclear translocation assay

    PMID:25458011

    Open questions at the time
    • Phosphorylation sites on Myc targeted by Eya1 not mapped
    • Whether SIX2-dependent Eya1 nuclear translocation requires direct physical interaction or an intermediary not resolved
  9. 2014 High

    Demonstrating that Osr1 and Six2 synergistically prevent differentiation—with Osr1 specifically stabilizing TCF–Groucho repressor complexes—dissected the division of labor among transcription factors maintaining the progenitor state.

    Evidence Conditional knockout, Co-IP, Wnt4 enhancer reporter in vivo, epistasis

    PMID:24598167

    Open questions at the time
    • Whether Six2 directly stabilizes TCF–Groucho or acts independently not resolved
    • Functional redundancy between Six2 and Osr1 at the chromatin level not tested
  10. 2014 Medium

    Showing that SIX2 represses E-cadherin via Zeb2 upregulation and Cdh1 promoter methylation to drive breast cancer metastasis revealed that SIX2 reactivates developmental EMT programs in cancer.

    Evidence Overexpression/knockdown, methylation assays, in vivo metastasis model, epistasis rescue

    PMID:25348955

    Open questions at the time
    • Whether SIX2 directly binds Zeb2 regulatory elements or acts indirectly via miRNAs not fully resolved
    • Generalizability beyond breast cancer cell lines not established
  11. 2016 High

    Notch signaling was shown to be necessary and sufficient for SIX2 downregulation during nephron progenitor differentiation, placing Notch as an upstream off-switch for the SIX2-maintained progenitor state.

    Evidence Conditional gain- and loss-of-function Notch pathway genetics in mouse kidney

    PMID:27993993

    Open questions at the time
    • Whether Notch directly represses Six2 transcription or acts through intermediary factors not determined
    • Interplay between Notch and Wnt signals at the Six2 locus not clarified
  12. 2016 Medium

    ChIP-based identification of Smurf1 and GDNF as direct SIX2 targets in dopaminergic neurons, regulated through an Akt1/Eya1/Six2 phosphorylation cascade, extended the SIX2 functional repertoire to neuroprotection.

    Evidence ChIP-seq, ChIP-qPCR, knockdown/overexpression, in vivo 6-OHDA lesion model

    PMID:27148690

    Open questions at the time
    • In vivo relevance of Six2 in dopaminergic neuron survival under physiological conditions not established
    • Structural basis of Eya1-mediated Six2 dephosphorylation unknown
  13. 2017 Medium

    Genetic lineage tracing identified SIX2-expressing cells as a dynamic subset of second heart field progenitors whose progressive allocation builds the right ventricle and pulmonary trunk, demonstrating a cardiac developmental role.

    Evidence Six2-Cre lineage tracing, conditional cell ablation, Shh deletion epistasis

    PMID:28122228

    Open questions at the time
    • Transcriptional targets of SIX2 in cardiac progenitors unknown
    • Whether SIX2 is required cell-autonomously in heart progenitors not tested
  14. 2017 Medium

    Haploinsufficiency studies revealed that reducing Six2 dosage paradoxically increases progenitor proliferation and final nephron number via elevated MYC, demonstrating that Six2's self-renewal and proliferation-control functions are separable by gene dosage.

    Evidence Quantitative morphometry, EdU labeling, Western blot, transcriptional profiling, Fgf20 epistasis

    PMID:29217079

    Open questions at the time
    • Mechanism by which reduced Six2 elevates MYC not determined
    • Whether this dosage effect is relevant to human nephron endowment variation unknown
  15. 2019 Medium

    ChIP demonstrated SIX2 directly binds the Sox2 Srr2 enhancer to activate a Sox2→Nanog stemness cascade in triple-negative breast cancer, establishing a direct transcriptional mechanism for SIX2-driven cancer stem cell maintenance.

    Evidence ChIP, enhancer reporter, overexpression/knockdown, in vivo metastasis model in TNBC

    PMID:30606720

    Open questions at the time
    • Whether SIX2 occupancy at Sox2 enhancer requires cofactors (e.g., Eya family) in cancer cells not tested
    • Relevance to non-breast cancer contexts not established
  16. 2020 Medium

    Functional studies in stem cell–derived β cells and human islets demonstrated that SIX2 is required for glucose-stimulated insulin secretion, calcium flux, and mitochondrial respiration, revealing an essential role in mature β-cell function distinct from its developmental progenitor role.

    Evidence KD/KO in hESC-derived SC-β cells and primary human islets, dynamic insulin secretion, calcium imaging, Seahorse assay, ATAC-seq

    PMID:32460030 PMID:33446570

    Open questions at the time
    • Direct SIX2 target genes mediating metabolic and electrophysiological effects in β cells not fully characterized
    • Whether SIX2 loss affects β-cell identity or only function not resolved
  17. 2021 High

    Identifying SIX2 interaction with the Brg1-SWI/SNF complex and showing that Six2 is required for Brg1 recruitment to nephron progenitor enhancers established a chromatin-remodeling mechanism for SIX2-dependent transcriptional activation.

    Evidence Tagged knock-in Co-IP, genome-wide ChIP, in vivo enhancer reporter, conditional knockout

    PMID:34716243

    Open questions at the time
    • Whether SIX2 directly contacts Brg1 or acts through Eya1 as a bridge not resolved
    • Genome-wide set of SIX2-dependent SWI/SNF-remodeled loci not comprehensively mapped
  18. 2022 Medium

    Genome-wide binding comparison between Six1 and Six2 showed that Six1 occupies only a small subset of Six2 target sites and fails to rescue proliferation and survival defects in Six2-null kidneys, establishing that paralog-specific binding underlies non-redundant functions.

    Evidence Conditional rescue genetics, genome-wide ChIP, cell proliferation/death assays

    PMID:35178390

    Open questions at the time
    • Sequence or structural determinants of SIX2-specific binding not identified
    • Cofactor differences that could explain selective occupancy not explored
  19. 2025 Medium

    Biochemical identification of TRIM21 as the E3 ligase catalyzing K48-ubiquitination at K82/K89/K97 of SIX2 established the first defined proteolytic regulatory mechanism controlling SIX2 protein levels.

    Evidence Co-IP, in vitro ubiquitination assay, K-to-R mutagenesis, proteasome inhibitor rescue

    PMID:40954199

    Open questions at the time
    • Signals or conditions triggering TRIM21-mediated SIX2 degradation not identified
    • Whether this pathway operates in normal development or only in cancer contexts not tested
    • No structural model of the TRIM21–SIX2 interface

Open questions

Synthesis pass · forward-looking unresolved questions
  • A structural basis for SIX2 DNA-binding specificity versus other SIX family members, the complete set of direct transcriptional targets in each progenitor context, and the signaling logic integrating Wnt, Notch, and Eya1 phosphatase inputs at the SIX2 locus remain unresolved.
  • No crystal or cryo-EM structure of SIX2 DNA-binding or protein-interaction domains
  • Genome-wide direct target validation across developmental and disease contexts incomplete
  • Quantitative signaling model integrating Wnt, Notch, and phosphorylation inputs on SIX2 activity not constructed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0003677 DNA binding 6
Localization
GO:0005634 nucleus 4
Pathway
R-HSA-1266738 Developmental Biology 6 R-HSA-162582 Signal Transduction 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-4839726 Chromatin organization 1
Partners
CTNNB1EYA1EYA4LEF1OSR1SMARCA4SMARCD1TRIM21
Complex memberships
Brg1-SWI/SNF complexSIX2–Lef/Tcf complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 Six2-expressing cap mesenchyme cells represent a multipotent nephron progenitor population that self-renews throughout kidney development; Six2 functions cell-autonomously to maintain progenitor status, as cap mesenchyme cells lacking Six2 activity contribute to ectopic nephron tubules via a Wnt9b-dependent inductive signal. Genetic lineage tracing (Six2-Cre), clonal analysis, conditional knockout, organ culture Cell stem cell High 18682239
2006 Six2 is required to maintain metanephric mesenchyme progenitor cells in an undifferentiated state by opposing Wnt inductive signals from the ureteric bud; functional inactivation of Six2 results in premature and ectopic epithelial differentiation and depletion of the progenitor pool, causing renal hypoplasia; gain of Six2 function prevents epithelial differentiation in organ culture. Loss-of-function mouse genetics, gain-of-function organ culture assay The EMBO journal High 17036046
2012 Six2 and β-catenin co-occupy shared cis-regulatory modules at Wnt4 and Fgf8 loci in nephron progenitors; Six2 and Lef/Tcf factors form a regulatory complex that promotes progenitor maintenance, while entry of β-catenin into this complex promotes nephrogenesis; Six2-dependent self-renewal and canonical Wnt/β-catenin-directed commitment operate through shared gene regulatory networks. Chromatin immunoprecipitation (ChIP), transcriptional profiling, in vitro and in vivo co-occupancy analysis, Lef/Tcf binding site mutagenesis Developmental cell High 22902740
2014 Eya1 interacts with Six2 and Myc to control self-renewing nephron progenitor cell activity; Six2 mediates translocation of Eya1 to the nucleus, where Eya1 uses its threonine phosphatase activity to control Myc phosphorylation/dephosphorylation in progenitor cells. Co-immunoprecipitation, conditional knockout, cell fate tracing, nuclear translocation assay, phosphatase activity assay Developmental cell High 25458011
2004 Six2 activates expression of the Gdnf gene through two binding sites in the Gdnf promoter that resemble homeobox consensus sequences; Six2 possesses a transcriptional activation domain in its C-terminus and nuclear localization determinants in its Six domain; Six2 also binds and activates its own 930 bp promoter fragment. Promoter-reporter assay, binding site identification, transgenic LacZ reporter mice, protein domain analysis Mechanisms of development Medium 15327782
2014 Six2 is required to maintain Osr1 expression in the undifferentiated cap mesenchyme; Osr1 and Six2 act synergistically to prevent premature differentiation; Osr1 (but not Six2) enhances TCF interaction with Groucho family co-repressors, stabilizing TCF-Groucho repressor complexes to antagonize Wnt-directed nephrogenic differentiation. Conditional knockout, protein interaction co-IP, Wnt4 enhancer reporter assay in vivo, epistasis Development (Cambridge, England) High 24598167
2016 Notch signaling promotes differentiation of nephron progenitors by downregulating Six2; Notch signaling is necessary and sufficient for Six2 downregulation; nephron progenitors lacking Notch signaling fail to differentiate into any nephron segments. Conditional gain- and loss-of-function mouse genetics, immunofluorescence Development (Cambridge, England) High 27633993
2014 Six2 promotes breast cancer metastasis by repressing E-cadherin expression through transcriptional upregulation of Zeb2 (partly via a microRNA-mediated mechanism) and by stimulating promoter methylation of the Cdh1 gene; E-cadherin downregulation is required for Six2-enhanced soft agar growth and in vivo metastasis. Overexpression/knockdown, methylation assay, in vivo metastasis model, epistasis rescue experiment Cancer research Medium 25348955
2019 Six2 directly binds the Sox2 Srr2 enhancer, promoting Sox2 expression and downstream Nanog expression, thereby establishing a cancer stem cell program that enables metastatic colonization in triple-negative breast cancer models. ChIP, overexpression/knockdown, enhancer reporter assay, in vivo metastasis model Cancer research Medium 30606720
2008 Six2 is a direct downstream target of Hoxa2 in vivo; ectopic expression of Six2 in the absence of Hoxa2 contributes to the Hoxa2 mutant phenotype; Six2 acts redundantly downstream of Hoxa2 and mediates Hoxa2 control over the insulin-like growth factor pathway during branchial arch development. Genetic epistasis, in vivo loss-of-function, ectopic expression Development (Cambridge, England) Medium 18321982
2009 A single enhancer upstream of the Six2 coding sequence is responsible for both activation by Hox11 proteins in the developing kidney and repression by Hoxa2 in branchial arch and facial mesenchyme; differential activity is conferred by protein domains N- and C-terminal to the homeodomain, not by homeodomain differences; DNA-binding activity is required for both activation and repression. In vivo enhancer analysis, domain-swap mutagenesis, transgenic reporter mice Developmental biology Medium 19716816
2015 LIF activates STAT signaling, which binds a Stat consensus sequence in the Six2 proximal promoter to sustain SIX2 levels in metanephric mesenchyme progenitors; ROCKi attenuates LIF-induced differentiation activity of JNK; LIF/ROCKi combination upregulates Slug expression and activates YAP to maintain SIX2, PAX2, and SALL1. Promoter-reporter assay, ChIP (STAT binding), pathway inhibition, culture expansion model Stem cell reports Medium 26321142
2016 Six2 activity is required for formation of the pyloric sphincter by regulating a gene network including Bmp4, Bmpr1b, Nkx2.5, Sox9, and Gremlin in mammals. Loss-of-function mouse genetics, gene expression analysis Developmental biology Medium 19660448
2016 Six2 transcription factor mediates the protective effects of GDNF on damaged dopaminergic neurons by directly binding the CAGCTG promoter sequence of Smurf1 and regulating its expression, which in turn modulates p53 levels; the Akt1/Eya1/Six2 signaling cascade controls GDNF transcription in MES23.5 DA cells by direct Six2 binding to the GDNF promoter. ChIP-seq, ChIP-qPCR, knockdown/overexpression, in vivo 6-OHDA lesion model Cell death & disease Medium 27148690
2019 MES23.5 DA cells respond to early 6-OHDA injury by activating an Akt1/Eya1/Six2 signaling pathway; activated Akt1 phosphorylates Eya1, which then decreases Six2 phosphorylation; dephosphorylated Six2 promotes GDNF transcription by directly binding the GDNF promoter, conferring neuroprotection. ChIP-qPCR, phosphorylation assays, knockdown/overexpression, cell viability assays Journal of molecular neuroscience : MN Medium 31720997
2021 Eya1 and Six2 interact with the Brg1-based SWI/SNF chromatin-remodeling complex during kidney development; Brg1 occupies a distal enhancer of Eya1 driving nephron progenitor-specific expression; Brg1 enrichment to distal intronic enhancers of Pbx1 and a proximal promoter of Mycn requires Six2 activity, and these Brg1/Six2-bound enhancers govern nephron progenitor-specific expression. Co-immunoprecipitation (tagged knock-in), genome-wide ChIP, enhancer reporter assay in vivo, conditional knockout Journal of the American Society of Nephrology : JASN High 34716243
2021 SIX2 knockdown in human pancreatic islets impairs glucose-stimulated insulin secretion, cytoplasmic calcium flux, and mitochondrial respiration; SIX2 directly regulates the expression of genes governing β-cell insulin processing, glucose sensing, and electrophysiology, as determined by chromatin accessibility studies. shRNA knockdown, ATAC-seq (chromatin accessibility), functional secretion assays, transcriptome profiling Genes & development Medium 33446570
2020 SIX2 regulates functional maturation of stem cell-derived β cells; knockout or knockdown of SIX2 drastically limits glucose-stimulated insulin secretion, cytoplasmic calcium flux, and mitochondrial respiration, and reduces expression of key β-cell functional genes. KD/KO in hESC-derived SC-β cells, static and dynamic insulin secretion assays, calcium imaging, Seahorse metabolic assay Cell reports Medium 32460030
2017 Six2 marks a dynamic subset of second heart field progenitors whose descendants are successively allocated to regions of the heart from the right ventricle to the pulmonary trunk; global ablation of Six2+ progenitors results in right ventricular hypoplasia and pulmonary atresia; early-stage ablation of a small subset causes adult-onset cardiac hypertrophy; Six2 expression in cardiac progenitors depends partly on Shh signaling. Genetic lineage tracing, conditional cell ablation, Shh deletion epistasis Cell reports Medium 28122228
2017 SIX2 expression in prostate cancer promotes a stem-like to epithelial cell state switch via the Wnt/β-catenin signaling pathway; SIX2 depletion in androgen-independent PC-3 cells reduces nuclear β-catenin and decreases cancer-related properties including proliferation, colony formation, and metastasis in vitro and in vivo. SIX2 knockdown, chromatin accessibility (ATAC-seq), in vitro and in vivo functional assays, nuclear β-catenin measurement Nucleic acids research Medium 38554106
2019 Six2 directly binds the promoters of CYP4Z1 and CYP4Z2P to activate the ceRNA network between them, thereby activating the downstream PI3K/Akt and ERK1/2 pathways and maintaining breast cancer stemness. ChIP-seq, RNA-seq, lentiviral overexpression/knockdown, in vitro and in vivo stemness assays Journal of hematology & oncology Medium 30832689
2010 Six2 inactivation causes premature fusion of cranial base bones due to reduced chondrocyte proliferation and increased terminal differentiation; gain-of-function Six2 promotes cartilage development and growth, indicating Six2 controls general regulators of chondrocyte differentiation. Loss-of-function mouse genetics, gain-of-function experiments, histological analysis of chondrocyte differentiation Developmental biology Medium 20515681
2018 In Lowe syndrome patient-derived kidney cells (OCRL1 mutant), Six2 is substantially retained in the Golgi complex with reduced nuclear localization; OCRL1 knockout in HK2 cells recapitulates both ciliogenesis defects and Six2 retention in the Golgi, indicating OCRL1-mediated phosphoinositide regulation controls Six2 nuclear trafficking. iPSC differentiation, OCRL1 KO, immunofluorescence subcellular localization, ciliogenesis assay PloS one Medium 29444177
2025 TRIM21 acts as an E3 ubiquitin ligase that binds to SIX2 via its PRY-SPRY domain and catalyzes K48-type ubiquitination at lysine residues K82, K89, and K97, promoting SIX2 degradation via the ubiquitin-proteasome pathway; this modification attenuates breast cancer stemness and metastasis; SIX2 transcriptionally activates LGSN through direct binding to its promoter. Co-IP, ubiquitination assay, site-specific mutagenesis (K82/89/97 residues), proteasome inhibitor rescue, ChIP, gain/loss-of-function Oncogene Medium 40954199
2017 Six2 in Six2 heterozygotes paradoxically increases nephron progenitor proliferation (elevated EdU labeling, increased MYC protein and MYC target gene transcription) and final nephron number, demonstrating that Six2's role in progenitor proliferation versus self-renewal is separable by dosage. Quantitative morphometry, EdU labeling, Western blot, transcriptional profiling, genetic epistasis with Fgf20 KO Kidney international Medium 29217079
2022 Six1 and Six2 have divergent biochemical properties: forced expression of Six1 fails to rescue Six2-deficient kidney phenotype; Six1 mediates Eya1 nuclear translocation and inhibits premature epithelialization but fails to rescue proliferation defects and cell death caused by Six2 knockout; genome-wide binding shows Six1 selectively occupies a small subset of Six2 target sites. Conditional rescue genetics, genome-wide ChIP, cell proliferation/death assays, nuclear translocation assay Frontiers in cell and developmental biology Medium 35178390
2021 Six2 transcriptionally activates DDIT4, leading to mTOR inhibition, autophagy induction, and a shift from M1 to M2 microglial polarization; M2-polarized microglia release exosomes enriched in miR-3470b that suppress GREM1 in dopaminergic neurons, potentiating TGF-β signaling and rescuing neuronal apoptosis. RNA-seq, ChIP-qPCR, miRNA sequencing, exosome isolation/transfer, in vitro and in vivo (MPTP mouse) functional assays CNS neuroscience & therapeutics Low 41700504
2024 SIX2 directly regulates METTL9 expression (CUT&Tag); METTL9 binds SLC7A11 (Co-IP) to enhance its stability and reduce ferroptosis, thereby conferring sorafenib resistance in HCC cells; this SIX2-METTL9-SLC7A11 axis operates independently of the GPX4 pathway. CUT&Tag, Co-IP, overexpression/knockdown, ferroptosis assays, in vivo mouse tumor model NPJ precision oncology Low 40523929
2019 Six2 directly binds the Sox2 enhancer to promote Sox2 expression and RCC cell stemness, forming a Six2/Sox2 axis; overexpression of Sox2 rescues the inhibitory effects of Six2 knockdown on RCC stemness. ChIP, overexpression/knockdown rescue, spheroid formation assay FEBS open bio Low 31420918
2021 Six2 transcriptionally activates GDNF in dopaminergic cells and forms a transcription complex with Smarcd1 (a SWI/SNF complex member); Smarcd1 is recruited to the 2840-2933 bp region of the GDNF promoter via Six2; knockdown of Smarcd1 inhibits Six2-mediated GDNF expression and increases apoptosis of injured DA neurons. LC-ESI-ITMS/MS (interactome screen), Co-IP, ChIP, overexpression/knockdown, cell viability assay Neuroscience letters Low 34233203
2019 Zeb1 promotes Six2 promoter activity (luciferase assay) and Six2 expression in metanephric mesenchyme cells; Zeb1 and Six2 coregulate cell proliferation and apoptosis. Dual-luciferase assay, Western blot, RT-PCR, knockdown/overexpression, EdU and flow cytometry assays International journal of molecular sciences Low 27509493
2017 TGFβ type II receptor (TβRII) promotes Six2 expression through Smad3-mediated transcriptional regulation; Smad3 transcriptionally targets Six2 (bioinformatics + luciferase assay); knockdown of TβRII reduces Six2 expression and proliferation, and overexpression of Six2 partially rescues the proliferation defect. Luciferase assay, RT-PCR, Western blot, EdU proliferation assay, knockdown rescue International journal of molecular sciences Low 28420207
2026 EYA4 interacts with SIX2 to promote expression of p21 and accelerate cellular senescence in a p53-dependent manner; this effect is independent of EYA4 phosphatase activity. Co-IP, knockdown/overexpression, phosphatase-deficient mutant, promoter reporter assay, senescence assays Advanced biotechnology Low 41991886
2024 SIX2 directly binds the promoter of SIX2/PFN2; SIX2 directly activates PFN2 expression, and PFN2 in turn promotes SIX2 mRNA stability by recruiting RNA-binding protein YBX-1, activating the downstream MAPK/JNK pathway to enhance gastric cancer cell stemness. ChIP, RNA stability assay, IP-MS, Co-IP, JNK pathway inhibition, gain/loss-of-function Journal of translational medicine Low 39256760

Source papers

Stage 0 corpus · 84 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Six2 defines and regulates a multipotent self-renewing nephron progenitor population throughout mammalian kidney development. Cell stem cell 757 18682239
2006 Six2 is required for suppression of nephrogenesis and progenitor renewal in the developing kidney. The EMBO journal 377 17036046
2012 Six2 and Wnt regulate self-renewal and commitment of nephron progenitors through shared gene regulatory networks. Developmental cell 211 22902740
2014 Eya1 interacts with Six2 and Myc to regulate expansion of the nephron progenitor pool during nephrogenesis. Developmental cell 97 25458011
2004 The transcription factor Six2 activates expression of the Gdnf gene as well as its own promoter. Mechanisms of development 87 15327782
2014 Osr1 acts downstream of and interacts synergistically with Six2 to maintain nephron progenitor cells during kidney organogenesis. Development (Cambridge, England) 69 24598167
2019 Transcriptional factor six2 promotes the competitive endogenous RNA network between CYP4Z1 and pseudogene CYP4Z2P responsible for maintaining the stemness of breast cancer cells. Journal of hematology & oncology 67 30832689
2016 Notch signaling promotes nephrogenesis by downregulating Six2. Development (Cambridge, England) 56 27633993
2014 Homeoprotein Six2 promotes breast cancer metastasis via transcriptional and epigenetic control of E-cadherin expression. Cancer research 55 25348955
2020 Circular RNA 0007255 regulates the progression of breast cancer through miR-335-5p/SIX2 axis. Thoracic cancer 48 31962380
2017 Temporally Distinct Six2-Positive Second Heart Field Progenitors Regulate Mammalian Heart Development and Disease. Cell reports 44 28122228
2017 The YAP1/SIX2 axis is required for DDX3-mediated tumor aggressiveness and cetuximab resistance in KRAS-wild-type colorectal cancer. Theranostics 43 28435452
2008 Six2 functions redundantly immediately downstream of Hoxa2. Development (Cambridge, England) 41 18321982
2020 The FGF, TGFβ and WNT axis Modulate Self-renewal of Human SIX2+ Urine Derived Renal Progenitor Cells. Scientific reports 40 31959818
2019 SIX2 Mediates Late-Stage Metastasis via Direct Regulation of SOX2 and Induction of a Cancer Stem Cell Program. Cancer research 40 30606720
2019 Crucial and Overlapping Roles of Six1 and Six2 in Craniofacial Development. Journal of dental research 39 30905259
2012 SIX2 and CITED1, markers of nephronic progenitor self-renewal, remain active in primitive elements of Wilms' tumor. Journal of pediatric surgery 37 22703800
2020 SIX2 Regulates Human β Cell Differentiation from Stem Cells and Functional Maturation In Vitro. Cell reports 36 32460030
2010 Inactivation of Six2 in mouse identifies a novel genetic mechanism controlling development and growth of the cranial base. Developmental biology 36 20515681
2019 DNMT1 in Six2 Progenitor Cells Is Essential for Transposable Element Silencing and Kidney Development. Journal of the American Society of Nephrology : JASN 35 30850438
2021 SIX2 and SIX3 coordinately regulate functional maturity and fate of human pancreatic β cells. Genes & development 34 33446570
2015 Preferential Propagation of Competent SIX2+ Nephronic Progenitors by LIF/ROCKi Treatment of the Metanephric Mesenchyme. Stem cell reports 33 26321142
2013 Wnt and BMP signaling cooperate with Hox in the control of Six2 expression in limb tendon precursor. Developmental biology 33 23499659
2008 Misexpression of Six2 is associated with heritable frontonasal dysplasia and renal hypoplasia in 3H1 Br mice. Developmental dynamics : an official publication of the American Association of Anatomists 33 18570229
2009 Non-homeodomain regions of Hox proteins mediate activation versus repression of Six2 via a single enhancer site in vivo. Developmental biology 30 19716816
2017 Haploinsufficiency for the Six2 gene increases nephron progenitor proliferation promoting branching and nephron number. Kidney international 29 29217079
2012 Conditional expression of Wnt9b in Six2-positive cells disrupts stomach and kidney function. PloS one 29 22912798
2000 Structure, mapping and expression of the human gene encoding the homeodomain protein, SIX2. Gene 29 10773454
2017 Genome-wide meta-analysis in Japanese populations identifies novel variants at the TMC6-TMC8 and SIX3-SIX2 loci associated with HbA1c. Scientific reports 28 29170429
2009 Deficiency in Six2 during prenatal development is associated with reduced nephron number, chronic renal failure, and hypertension in Br/+ adult mice. American journal of physiology. Renal physiology 27 19193724
2016 MicroRNA-185 inhibits cell proliferation and epithelial-mesenchymal transition in hepatocellular carcinoma by targeting Six2. European review for medical and pharmacological sciences 25 27212161
2015 A new frontonasal dysplasia syndrome associated with deletion of the SIX2 gene. American journal of medical genetics. Part A 25 26581443
2014 SIX2 Effects on Wilms Tumor Biology. Translational oncology 24 25500091
2012 The pluripotent renal stem cell regulator SIX2 is activated in renal neoplasms and influences cellular proliferation and migration. Human pathology 24 22995329
2009 Six2 activity is required for the formation of the mammalian pyloric sphincter. Developmental biology 24 19660448
2019 Six2 promotes non-small cell lung cancer cell stemness via transcriptionally and epigenetically regulating E-cadherin. Cell proliferation 22 31012173
2017 Derivation and characterization of integration-free iPSC line ISRM-UM51 derived from SIX2-positive renal cells isolated from urine of an African male expressing the CYP2D6 *4/*17 variant which confers intermediate drug metabolizing activity. Stem cell research 22 29035842
2016 Transcription factor Six2 mediates the protection of GDNF on 6-OHDA lesioned dopaminergic neurons by regulating Smurf1 expression. Cell death & disease 22 27148690
2013 MiR-181b targets Six2 and inhibits the proliferation of metanephric mesenchymal cells in vitro. Biochemical and biophysical research communications 22 24055707
2016 Zeb1 Is a Potential Regulator of Six2 in the Proliferation, Apoptosis and Migration of Metanephric Mesenchyme Cells. International journal of molecular sciences 21 27509493
2010 Mutational analysis of HOXA2 and SIX2 in a Bronx population with isolated microtia. International journal of pediatric otorhinolaryngology 21 20542577
2017 Six2 Plays an Intrinsic Role in Regulating Proliferation of Mesenchymal Cells in the Developing Palate. Frontiers in physiology 18 29218017
2016 SIX2 haploinsufficiency causes conductive hearing loss with ptosis in humans. Journal of human genetics 15 27383657
2024 SIX2 promotes cell plasticity via Wnt/β-catenin signalling in androgen receptor independent prostate cancer. Nucleic acids research 13 38554106
2022 De novo SIX2 activation in human kidneys treated with neonatal kidney stem/progenitor cells. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 13 35913414
2021 Chromatin Remodelers Interact with Eya1 and Six2 to Target Enhancers to Control Nephron Progenitor Cell Maintenance. Journal of the American Society of Nephrology : JASN 13 34716243
2019 Six2 regulates Pax9 expression, palatogenesis and craniofacial bone formation. Developmental biology 13 31765609
2014 miR181c promotes apoptosis and suppresses proliferation of metanephric mesenchyme cells by targeting Six2 in vitro. Cell biochemistry and function 13 25187057
2019 PPARG Negatively Modulates Six2 in Tumor Formation of Clear Cell Renal Cell Carcinoma. DNA and cell biology 12 31090452
2018 Kidney-differentiated cells derived from Lowe Syndrome patient's iPSCs show ciliogenesis defects and Six2 retention at the Golgi complex. PloS one 12 29444177
2016 Postembryonic Nephrogenesis and Persistence of Six2-Expressing Nephron Progenitor Cells in the Reptilian Kidney. PloS one 11 27144443
2015 Identification of distal enhancers for Six2 expression in pronephros. The International journal of developmental biology 11 26009236
2014 Down-regulated Six2 by knockdown of neurofibromin results in apoptosis of metanephric mesenchyme cells in vitro. Molecular and cellular biochemistry 9 24573885
2022 Six1 and Six2 of the Sine Oculis Homeobox Subfamily are Not Functionally Interchangeable in Mouse Nephron Formation. Frontiers in cell and developmental biology 8 35178390
2018 SIX2 gene haploinsufficiency leads to a recognizable phenotype with ptosis, frontonasal dysplasia, and conductive hearing loss. Clinical dysmorphology 8 29315086
2016 Six2 Is a Coordinator of LiCl-Induced Cell Proliferation and Apoptosis. International journal of molecular sciences 8 27618015
2024 Reduced Nephron Endowment in Six2-TGCtg Mice Is Due to Six3 Misexpression by Aberrant Enhancer-Promoter Interactions in the Transgene. Journal of the American Society of Nephrology : JASN 7 38447671
2022 Tet2- and Tet3- Mediated Cytosine Hydroxymethylation in Six2 Progenitor Cells in Mice Is Critical for Nephron Progenitor Differentiation and Nephron Endowment. Journal of the American Society of Nephrology : JASN 7 36522157
2019 MES23.5 DA Immortalized Neuroblastoma Cells Self-protect Against Early Injury by Overexpressing Glial Cell-derived Neurotrophic Factor via Akt1/Eya1/Six2 Signaling. Journal of molecular neuroscience : MN 7 31720997
2024 Six2 regulates the malignant progression and 5-FU resistance of hepatocellular carcinoma through the PI3K/AKT/mTOR pathway and DNMT1/E-cadherin methylation mechanism. Neoplasma 6 39556430
2024 Microglial SIX2 suppresses lipopolysaccharide (LPS)-induced neuroinflammation by up-regulating FXYD2 expression. Brain research bulletin 4 38688414
2024 The SIX2/PFN2 feedback loop promotes the stemness of gastric cancer cells. Journal of translational medicine 4 39256760
2023 NIK-mediated reactivation of SIX2 enhanced the CSC-like traits of hepatocellular carcinoma cells through suppressing ubiquitin-proteasome system. Environmental toxicology 4 37461228
2021 Smarcd1 antagonizes the apoptosis of injured MES23.5 DA cells by enhancing the effect of Six2 on GDNF expression. Neuroscience letters 4 34233203
2022 [Effects of transcription factor SIX2 gene on the proliferation of bovine skeletal muscle satellite cells]. Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology 3 37308406
2020 Generation and characterization of Six2 conditional mice. Genesis (New York, N.Y. : 2000) 3 32277572
2019 Constructing an Isogenic 3D Human Nephrogenic Progenitor Cell Model Composed of Endothelial, Mesenchymal, and SIX2-Positive Renal Progenitor Cells. Stem cells international 3 31191670
2019 Transcription factor Six2 induces a stem cell-like phenotype in renal cell carcinoma cells. FEBS open bio 3 31420918
2017 TβRII Regulates the Proliferation of Metanephric Mesenchyme Cells through Six2 In Vitro. International journal of molecular sciences 3 28420207
2017 Six2 is involved in GATA1-mediated cell apoptosis in mouse embryonic kidney-derived cell lines. In vitro cellular & developmental biology. Animal 3 28842839
2018 Gulo regulates the proliferation, apoptosis and mesenchymal-to-epithelial transformation of metanephric mesenchyme cells via inhibiting Six2. Biochemical and biophysical research communications 2 30219227
2013 [Expression and promoter methylation of SIX2 gene in peripheral blood of pediatric patients with nephroblastoma]. Zhonghua yi xue za zhi 2 24124738
2011 Osmoregulatory defect in adult mice associated with deficient prenatal expression of six2. American journal of physiology. Regulatory, integrative and comparative physiology 2 21653879
2025 TRIM21-mediated ubiquitination of SIX2 attenuates breast cancer stemness via LGSN suppression. Oncogene 1 40954199
2025 Human Urine-Derived SIX2-Positive Renal Progenitor Cells Partially Improve Kidney Fibrosis by Paracrine Signaling. Stem cells and development 1 41168982
2023 Reduced nephron endowment in the common Six2-TGC mouse line is due to Six3 misexpression by aberrant enhancer-promoter interactions in the transgene. bioRxiv : the preprint server for biology 1 37873415
2021 MicroRNA-185 inhibits cell proliferation and epithelial-mesenchymal transition in hepatocellular carcinoma by targeting Six2. European review for medical and pharmacological sciences 1 34109599
2019 Correction to: Transcriptional factor six2 promotes the competitive endogenous RNA network between CYP4Z1 and pseudogene CYP4Z2P responsible for maintaining the stemness of breast cancer cells. Journal of hematology & oncology 1 31651345
2026 SIX2-Mediated Microglial M2 Polarization and Exosomal miR-3470b Delivery Protect Dopaminergic Neurons in Parkinson's Disease. CNS neuroscience & therapeutics 0 41700504
2026 EYA4 promotes cellular senescence by enhancing P21 transcription through interaction with SIX2. Advanced biotechnology 0 41991886
2025 Targeting SIX2 as a novel sensitization strategy of sorafenib treatment on advanced hepatocellular carcinoma through modulating METTL9-SLC7A11 axis. NPJ precision oncology 0 40523929
2025 OSR1 and SIX2 drive divergent transcriptional programs in human kidney cells: implications for regeneration and tumorigenesis. Frontiers in bioengineering and biotechnology 0 41112069
2025 Modelling APOL1-mediated kidney inflammation and fibrosis using a partially reprogrammed urine-derived SIX2-positive renal progenitor cell line. Stem cell research & therapy 0 41225540
2024 RETRACTION: Six2 Promotes Non-Small Cell Lung Cancer Cell Stemness Via Transcriptionally and Epigenetically Regulating E-Cadherin. Cell proliferation 0 38804816