Affinage

HES5

Transcription factor HES-5 · UniProt Q5TA89

Length
166 aa
Mass
18.2 kDa
Annotated
2026-04-28
65 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HES5 is a basic helix-loop-helix (bHLH) transcriptional repressor that serves as a central downstream effector of Notch signaling, maintaining neural stem and progenitor cell identity by repressing pro-differentiation genes across multiple tissues including the brain, retina, inner ear, vasculature, and thymus. HES5 directly represses target gene promoters—including those of Math1/Atoh1, Hmga1/2, Fbw7β, LIGHT/TNFSF14, and HES1—in some cases by recruiting SIRT1 to mediate histone deacetylation, and its own transcription is activated by Sox2, SOX4, SOX15, and Gcm1/2 (via DNA demethylation) while being repressed by FEZF1/2 and Sox21, integrating multiple upstream signals into Notch pathway output (PMID:10205173, PMID:20431123, PMID:22956844, PMID:29352015, PMID:34689159, PMID:23776410). In neural progenitors, endogenous HES5 protein levels oscillate dynamically, and the transition from aperiodic to periodic oscillation patterns correlates with cell fate decisions between distinct neuronal subtypes (PMID:31249377, PMID:34031978). Beyond neurogenesis, HES5 promotes Müller glial fate in the retina, suppresses hair cell overproduction in the inner ear, contributes to arterial identity in brain vasculature, modulates T- versus B-cell fate, and instructs cardiac commitment from early mesoderm (PMID:10821751, PMID:11425898, PMID:23871867, PMID:18048645, PMID:28648899).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1995 High

    Identifying that the HES5 promoter contains neural precursor cell-specific elements established HES5 as a gene with tightly restricted transcriptional regulation, raising the question of what upstream pathways control its expression.

    Evidence Promoter-reporter transfections and gel-shift assays in neural versus non-neural cell lines

    PMID:7836401

    Open questions at the time
    • Identity of the neural precursor-specific transcription factor binding the GC-rich element was not determined
    • In vivo relevance of the promoter elements was not tested
  2. 1999 High

    Genetic epistasis using Hes1/Hes5 double-null neural precursors demonstrated that HES5 (redundantly with HES1) is an essential downstream effector of Notch-mediated inhibition of neuronal differentiation, resolving HES5's position in the Notch pathway.

    Evidence Retroviral constitutively active Notch expression in wild-type, single-null, and double-null mouse neural precursors

    PMID:10205173

    Open questions at the time
    • Direct transcriptional targets of HES5 in this context were not identified
    • Whether HES5 acts solely as a transcriptional repressor or has additional mechanisms was unknown
  3. 2000 High

    Reciprocal gain- and loss-of-function in the retina showed that HES5 promotes Müller glial cell fate at the expense of neurons, extending its function beyond simply blocking neuronal differentiation to actively specifying glial identity.

    Evidence Retroviral Hes5 misexpression and Hes5-deficient mouse retina analysis with cell-type quantification

    PMID:10821751

    Open questions at the time
    • Whether HES5 directly represses retinal neuron-specific transcription factors was not shown
    • The relative contributions of HES5 versus HES1 in retinal gliogenesis were not fully resolved
  4. 2001 High

    Two studies simultaneously expanded HES5's roles: one showed HES5 maintains neural stem cell self-renewal in the telencephalon, and another demonstrated it negatively regulates hair cell differentiation in the inner ear by restraining Math1, establishing HES5 as a multi-tissue Notch effector.

    Evidence Neurosphere assays in Hes1/Hes5 double-null embryos; Hes5 knockout cochlear and vestibular histology with Math1 in situ hybridization

    PMID:11399758 PMID:11425898

    Open questions at the time
    • Whether HES5 directly binds and represses Math1 promoter was not demonstrated at this stage
    • Mechanisms distinguishing HES5's stem cell maintenance function from its anti-differentiation role were unclear
  5. 2005 Medium

    Discovery of a cross-repressive circuit between Hes5 and Hes6 in chick neural progenitors revealed that HES5 participates in oscillatory regulatory loops rather than acting as a simple static repressor, foreshadowing later dynamic studies.

    Evidence Reciprocal gain- and loss-of-function in chick neural tube with in situ hybridization

    PMID:15893982

    Open questions at the time
    • Temporal dynamics of the Hes5/Hes6 circuit were not resolved at single-cell resolution
    • Whether this circuit operates identically in mammalian systems was not confirmed
  6. 2007 Medium

    Two discoveries extended HES5 function beyond neurogenesis: Hes5-null thymocytes showed impaired T-cell fate specification at intermediate Notch ligand levels, and Hes5 was identified as a negative regulator of contextual fear memory downstream of SGK1, broadening HES5's biological roles.

    Evidence Hes5 knockout bone marrow progenitor cultures with graded Delta1; shRNA/overexpression of Hes5 in hippocampal neurons with fear conditioning

    PMID:17241237 PMID:18048645

    Open questions at the time
    • Direct transcriptional targets of HES5 in T-cell fate specification were not identified
    • Mechanism connecting HES5 repression to memory consolidation at the molecular level was not elucidated
    • The SGK1-HES5 axis lacks independent replication
  7. 2010 High

    ChIP and genetic epistasis showed FEZF1/2 directly bind and repress the Hes5 promoter, and Hes5 loss rescues the neurogenesis defect of Fezf1/2 knockouts, establishing the first direct upstream transcriptional repressor of HES5 and placing HES5 as a node integrating FEZF and Notch inputs.

    Evidence ChIP/promoter binding; Fezf1/Fezf2/Hes5 compound knockout mouse cortex analysis

    PMID:20431123

    Open questions at the time
    • Whether FEZF-mediated Hes5 repression is direct at endogenous chromatin in all cortical zones was not resolved
    • Other FEZF targets that may contribute independently were not excluded
  8. 2011 High

    Gcm1/2 were shown to initiate Hes5 expression in the neuroepithelium through replication-independent DNA demethylation, revealing an epigenetic activation mechanism for HES5 at the onset of neural stem cell programming.

    Evidence Gcm1/Gcm2 double knockout mouse; bisulfite sequencing; neurosphere assays

    PMID:21765423

    Open questions at the time
    • The specific demethylase recruited by Gcm proteins to the Hes5 locus was not identified
    • Whether this epigenetic mechanism is conserved in human neural development was not tested
  9. 2012 High

    Sox21 was shown by ChIP to directly bind and repress the Hes5 promoter, with Sox21 loss impairing neural progenitor transitions in the hippocampus; co-overexpression placed HES5 as the key effector mediating Sox21's influence on progenitor differentiation at the Notch-Sox intersection.

    Evidence Sox21 knockout mouse hippocampus; ChIP for Sox21 at Hes5 promoter; Hes5/Sox21 co-overexpression; BrdU/marker analysis

    PMID:22956844

    Open questions at the time
    • Whether Sox21 repression of Hes5 involves chromatin remodeling was not determined
    • The precise molecular mechanism of Sox21-Hes5 epistasis at the protein level was not resolved
  10. 2013 High

    HES5 was found to directly repress Fbw7β transcription, creating a positive feedback loop that stabilizes Notch signaling; genetic rescue of Fbw7 haploinsufficiency by Hes5 loss in intestinal and neural stem cells demonstrated the physiological relevance of this loop.

    Evidence Fbw7/Hes5 compound mutant mice; luciferase reporter assays; computational modeling

    PMID:23776410

    Open questions at the time
    • Whether HES5 binds the Fbw7β promoter directly (by ChIP at endogenous locus) was not shown in this study
    • Contribution of other HES family members to Fbw7 regulation was not fully excluded
  11. 2013 Medium

    Hes5 knockdown was shown to enhance hair cell regeneration following aminoglycoside damage in the vestibular system, and Hes1/Hes5 conditional endothelial knockout revealed requirements for brain vascular remodeling and arterial identity, further expanding HES5's tissue-specific roles.

    Evidence siRNA delivery to damaged mouse utricle; endothelial-specific Hes1/Hes5 conditional knockout with vascular and arterial marker analysis

    PMID:23439501 PMID:23871867

    Open questions at the time
    • Whether HES5 alone is sufficient for vascular remodeling or always acts redundantly with HES1 was not resolved
    • Direct HES5 target genes in endothelial cells were not identified
  12. 2017 High

    Reciprocal gain- and loss-of-function in the neocortex demonstrated that HES5 controls the timing of deep-to-superficial layer neurogenesis transitions and gliogenesis onset by directly repressing Hmga1/2, identifying a new class of HES5 target genes that regulate chromatin architecture.

    Evidence Hes5-overexpressing transgenic and Hes5 knockout mice; promoter reporter assays; cortical layer marker immunostaining

    PMID:28851724

    Open questions at the time
    • Whether HES5 recruits specific co-repressors to the Hmga1/2 promoters was not determined
    • How Hmga chromatin remodeling feeds back on HES5 dynamics was not addressed
  13. 2018 High

    Sox2 and SOX4 were each shown by independent studies to directly activate Hes5 transcription—Sox2 via promoter binding (ChIP in PNS/CNS) and SOX4 via epistatic rescue—consolidating the picture of HES5 as a transcriptional node integrating multiple SOX family inputs.

    Evidence ChIP for Sox2 at Hes5 promoter in olfactory epithelium and CNS plus Sox2 cKO; SOX4 knockdown/overexpression with Hes5 rescue in NSCs

    PMID:29352015 PMID:30343100

    Open questions at the time
    • Whether Sox2 and SOX4 bind simultaneously or compete at the Hes5 locus was not tested
    • SOX4-HES5 axis relies on a single-lab inducible system without ChIP confirmation of direct SOX4 binding
  14. 2019 High

    Single-cell live imaging of endogenous HES5 protein revealed dynamic oscillations in neural progenitors whose periodicity increases as cells approach differentiation, establishing that HES5 expression dynamics—not just levels—encode cell fate information.

    Evidence Endogenous HES5 fluorescent reporter in embryonic mouse spinal cord; absolute protein quantification; mathematical modeling

    PMID:31249377

    Open questions at the time
    • Whether oscillation frequency is instructive or merely correlative for fate choice requires perturbation of oscillation parameters independently of mean level
    • Upstream drivers that set oscillation period were not identified
  15. 2021 High

    Tissue-level imaging showed HES5 forms spatially periodic microclusters in the spinal cord whose temporal dynamics depend on Notch but whose spatial periodicity does not, separating spatial patterning from temporal signaling and suggesting an intrinsic tissue-organizing principle.

    Evidence Ex vivo live imaging of HES5 reporter; pharmacological Notch inhibition (DAPT); computational modeling

    PMID:34031978

    Open questions at the time
    • The molecular basis of Notch-independent spatial periodicity is unknown
    • Whether HES5 microclusters exist in tissues beyond the spinal cord was not tested
  16. 2021 Medium

    The mechanism of HES5-mediated transcriptional repression was clarified: HES5 directly binds the LIGHT/TNFSF14 promoter and recruits SIRT1 for histone H3/H4 deacetylation, establishing SIRT1-dependent chromatin remodeling as one effector mechanism of HES5 repression.

    Evidence ChIP for HES5 at LIGHT promoter; co-immunoprecipitation of HES5 and SIRT1; SIRT1 inhibition rescue

    PMID:34689159

    Open questions at the time
    • Whether SIRT1 recruitment is a general mechanism for all HES5 target genes or target-specific was not determined
    • Structural basis of HES5-SIRT1 interaction is unknown
  17. 2023 Medium

    SOX15 was identified as another direct transcriptional activator of Hes5 via a distal enhancer, and SOX15 loss impaired neural fate commitment with failure to upregulate Hes5, adding yet another SOX family member to the growing list of HES5 activators.

    Evidence ChIP for SOX15 at Hes5 distal enhancer; SOX15 knockout ESC neural differentiation

    PMID:36764520

    Open questions at the time
    • Whether the SOX15-bound distal enhancer interacts with the proximal promoter via chromatin looping was not shown
    • Redundancy with Sox2 at this enhancer was not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: what determines whether HES5 oscillations are instructive versus permissive for specific fate choices; what is the structural basis of HES5's selectivity among target promoters; and whether the SIRT1 co-repressor mechanism generalizes across HES5's diverse tissue contexts.
  • No structural model of HES5 bound to DNA or co-repressor exists
  • Causal perturbation of oscillation parameters independently of mean HES5 level has not been achieved
  • Genome-wide direct target identification by ChIP-seq in primary neural progenitors is lacking

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 1
Pathway
R-HSA-1266738 Developmental Biology 9 R-HSA-162582 Signal Transduction 5 R-HSA-112316 Neuronal System 2 R-HSA-4839726 Chromatin organization 2
Partners
FEZF1FEZF2HES1HES6SIRT1SOX2SOX21SOX4

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Hes1 and Hes5 are essential downstream effectors of Notch signaling in mammalian neuronal differentiation; constitutively active Notch fails to inhibit neuronal differentiation in Hes1/Hes5 double-null neural precursor cells, but retains this ability in single-null backgrounds, placing Hes1 and Hes5 genetically downstream of Notch in this pathway. Retroviral misexpression of constitutively active Notch in wild-type, Hes1-null, Hes5-null, and Hes1/Hes5 double-null mouse neural precursor cells; genetic epistasis The EMBO journal High 10205173
2001 Hes1 and Hes5 are required for maintenance of neural stem cells in the embryonic telencephalon; misexpression keeps cells undifferentiated and loss of both genes results in fewer and smaller neurospheres, indicating a role in neural stem cell self-renewal rather than gliogenesis in this context. Retroviral misexpression of Hes1/Hes5 in telencephalic cells; neurosphere assay in Hes1/Hes5 single and double null mouse embryos The Journal of biological chemistry High 11399758
2000 Hes5 promotes Müller glial cell fate in the mouse retina at the expense of neurons; misexpression of Hes5 via retrovirus significantly increases the glial cell population, while Hes5-deficient retina shows 30-40% reduction in Müller glial cell number without affecting cell survival. Retroviral misexpression of Hes5 in mouse retina; analysis of Hes5-deficient retina Development (Cambridge, England) High 10821751
2001 Hes5 (and Hes1) act as negative regulators of hair cell differentiation in the mammalian inner ear; Hes5-null mice show a significant increase in outer hair cell numbers in the cochlea and supernumerary hair cells in the vestibular system, accompanied by upregulation of the positive regulator Math1. Analysis of Hes5 knockout mice by cochlear and vestibular histology; in situ hybridization for Math1 The Journal of neuroscience High 11425898
1995 The HES5 promoter contains multiple GC stretches that are bound by a neural precursor cell-specific protein and drive expression specifically in neural precursor cells, but not in differentiated neurons, glia, or fibroblasts; this element was identified as the neural precursor cell-specific promoter element. Transient transfection of promoter-reporter constructs in neural and non-neural cell lines; gel mobility shift assay; primer extension and RT-PCR for transcription start site mapping The Journal of biological chemistry High 7836401
2003 Hes5, unlike Hes1, does not promote astrocyte differentiation in glial restricted precursors (GRPs); instead, Hes5 overexpression inhibits both astrocyte and oligodendrocyte differentiation from GRPs, while Hes1 overexpression drives astrocyte fate and downregulates oligodendrocyte transcription factors. Hes1 and Hes5 overexpression in GRPs; immunostaining for glial markers (GFAP, GalC, CNPase, MBP); RT-PCR for Nkx2.2, Olig1, Mash1 Developmental dynamics Medium 12666205
2005 Hes5 and Hes6 form a negative regulatory circuit during neurogenesis: hes5 activity represses hes6-2 expression, while hes6-2 can in turn repress hes5 transcription; this cross-regulatory circuitry modulates cycles of Notch activity in neural progenitors and controls neuronal commitment. In situ hybridization; gain- and loss-of-function in chick neural tube; epistasis experiments Developmental biology Medium 15893982
2010 FEZF1 and FEZF2 zinc finger transcriptional repressors directly bind and repress the Hes5 promoter; loss of Fezf1/Fezf2 leads to upregulation of Hes5 and downregulation of neurogenin 2 (a known Hes5 target), impairing cortical neurogenesis; this defect is suppressed by Hes5 loss, placing Hes5 downstream of Fezf1/2 in the neurogenesis pathway. ChIP/promoter binding assay; Fezf1/Fezf2 knockout analysis; Hes5 knockout epistasis; in situ hybridization Development (Cambridge, England) High 20431123
2011 Mammalian Gcm1 and Gcm2 initiate Hes5 expression in the neuroepithelium through active DNA demethylation independently of DNA replication; loss of both Gcm genes impairs Hes5 upregulation and subsequent neural stem cell induction, placing Gcm genes upstream of Hes5 in the initial activation of the neural stem cell program. Gcm1/Gcm2 double knockout mouse analysis; bisulfite sequencing; neurosphere assay Nature neuroscience High 21765423
2012 Sox21 directly binds the Hes5 promoter and transcriptionally represses Hes5 expression; loss of Sox21 in the adult hippocampus impairs the transition of neural progenitors from type 2a to type 2b and reduces neuron production; simultaneous overexpression of Hes5 and Sox21 demonstrates that Hes5 is a key downstream effector of Sox21 at the Notch/Sox pathway intersection. Sox21 knockout mouse; ChIP for Sox21 binding at Hes5 promoter; Hes5 and Sox21 co-overexpression; BrdU/marker immunostaining The Journal of neuroscience High 22956844
2013 HES5 directly represses transcription of Fbw7β (an E3 ubiquitin ligase component), creating a positive feedback loop that sustains Notch signaling; Fbw7 haploinsufficiency impairs intestinal progenitor and neural stem cell differentiation, and these phenotypes are rescued by concomitant Hes5 inactivation. Fbw7/Hes5 compound mutant mice; luciferase reporter assays; in silico modeling; epistasis analysis PLoS biology High 23776410
2017 Hes5 regulates the timing of transitions between deep-layer and superficial-layer neurogenesis and the onset of gliogenesis in the mouse neocortex; Hes5 overexpression shifts these transitions earlier and is accompanied by downregulation of Hmga1/2 genes, while Hes5 knockout delays them with upregulation of Hmga1/2; Hes5 directly suppresses Hmga1/2 promoter activity. Hes5-overexpressing transgenic mice; Hes5 knockout mice; promoter reporter assays; cortical layer marker analysis Development (Cambridge, England) High 28851724
2013 siRNA-mediated knockdown of Hes5 in the mouse utricle following aminoglycoside damage significantly increases the number of hair cells generated, demonstrating that Hes5 suppresses transdifferentiation of supporting cells into hair cells during vestibular regeneration. siRNA delivery to mouse utricle in vivo; hair cell counting after aminoglycoside damage Molecular therapy Medium 23439501
2007 Hes5 is required for appropriate T- versus B-cell fate decisions in the thymus in response to intermediate and low levels of Notch ligand; Hes5-deficient thymuses show increased generation of B-cell precursors, and Hes5-deficient progenitors misread intermediate/low Notch ligand densities while responding appropriately to high densities. Hes5 knockout mice; bone marrow progenitor cultures with immobilized Delta1 ligand at varying densities; flow cytometry Blood Medium 18048645
2008 Cdc42-mTOR signaling pathway, activated downstream of FGF and Delta/Notch, upregulates Hes5 (and Pax6) expression to maintain neural progenitor cell identity; constitutively active Cdc42(F28L) is sufficient to upregulate Hes5 in P19 cells even without retinoic acid, and inhibition of this pathway reduces Hes5 expression. Chemical inhibitors of FGF/Notch/mTOR pathways; RNAi; constitutively active Cdc42 mutant overexpression in P19 cells; immunofluorescence and RT-PCR The Journal of biological chemistry Medium 19097998
2019 Single-cell live imaging of endogenous HES5 protein in embryonic mouse spinal cord reveals that HES5 levels fluctuate both aperiodically and periodically in dividing neural progenitors; as cells transition toward differentiation, HES5 oscillations become more frequently periodic with a transient increase in fold-expression change, and this dynamic pattern correlates with interneuron versus motor neuron cell fate decisions. Live single-cell imaging of endogenous HES5 fluorescent reporter; absolute protein quantification; mathematical modeling Nature communications High 31249377
2021 HES5 expression forms spatially periodic microclusters of 4-6 cells along the dorsoventral axis of the developing mouse spinal cord with supra-ultradian temporal dynamics; Notch signaling is required for temporal dynamics but not spatial periodicity of HES5 clusters; this tissue-level organization enables stable selection of differentiating cells. Ex vivo live imaging of HES5 reporter in spinal cord; pharmacological Notch inhibition; computational modelling Molecular systems biology High 34031978
2018 SOX4 directly induces Hes5 transcription in neural stem cells, and Hes5 mediates SOX4's inhibitory effect on oligodendrocyte differentiation; conditional Hes5 overexpression rescues the increased oligodendrocyte differentiation caused by SOX4 depletion, placing Hes5 as an effector of SOX4-driven oligodendrocyte suppression. SOX4 knockdown and conditional overexpression in NSCs; Hes5 overexpression rescue; flow cytometry for oligodendrocyte markers; doxycycline-inducible system Stem cell research Medium 30343100
2020 HES5 reduces hepatocellular carcinoma cell migration and clonogenicity; the patient-derived HES5-R31G mutation abolishes DNA binding and greatly reduces nuclear localization, rendering HES5 non-functional; HES5 directly inhibits HES1 transcription (negative feedback) and downregulates MYC targets ODC1 and LDHA. In vitro functional assays (migration, colony formation); analysis of HES5-R31G mutant protein; luciferase reporter; orthotopic mouse model Oncogene Medium 32055024
2014 HES5 acts as a key mediator of Wnt-3a-induced neuronal differentiation via a β-catenin-independent mechanism; Wnt-3a causes sustained HES5 repression and MASH1 upregulation, and HES5 overexpression blocks both Wnt-3a- and γ-secretase inhibitor-induced neuronal differentiation with strong MASH1 downregulation in human neural progenitor cells. HES5 overexpression and siRNA knockdown in hNPCs; Wnt-3a treatment; RT-PCR; GSK3β inhibitor and Dkk-1 controls; neuronal differentiation assay Stem cells and development Medium 24548083
2017 HES5 promotes cardiac over primitive erythroid fate specification from early mesoderm; a pulse of Hes5 instructs cardiac commitment and upregulates Isl1 while downregulating the hematopoietic regulator Scl, but sustained HES5 expression after lineage specification impairs progression to contracting cardiomyocytes. Loss- and gain-of-function experiments in mouse embryonic stem cells; gene expression analysis; cardiomyocyte differentiation assays Stem cell reports Medium 28648899
2021 HES5 directly binds the FBXW7 promoter to repress its transcription, leading to stabilization of TGIF1 and inactivation of TGF-β signaling in endometrial stromal cells; this HES5/FBXW7/TGIF1 axis inhibits hESC proliferation and invasion and alleviates endometriosis in a mouse model. Co-immunoprecipitation; dual-luciferase reporter assay; chromatin immunoprecipitation; mouse EMS model; siRNA knockdown FASEB journal Medium 33496006
2021 HES5 directly binds to the LIGHT/TNFSF14 promoter and recruits SIRT1 to deacetylate histone H3/H4, thereby repressing LIGHT transcription; this HES5-SIRT1 complex suppresses hepatocyte apoptosis in a fatty acid/NAFLD context. ChIP for HES5 binding at LIGHT promoter; co-immunoprecipitation of HES5 and SIRT1; HES5 overexpression/knockdown; SIRT1 inhibition Cell death discovery Medium 34689159
2016 HES5 directly interacts with STAT3 (by co-immunoprecipitation) and promotes STAT3 phosphorylation and downstream gene expression in non-small cell lung cancer cells; HES5 knockdown causes G0/G1 cell cycle arrest and reduces colony formation. Co-immunoprecipitation; HES5 siRNA knockdown; Western blot for p-STAT3; cell cycle analysis; colony formation assay Oncology reports Low 27878283
2023 SOX15 directly binds a distal enhancer of Hes5 to activate its transcription during neural differentiation of embryonic stem cells; SOX15 depletion leads to defective neural fate commitment, which is associated with failure to upregulate Hes5. ChIP for SOX15 binding at Hes5 enhancer; SOX15 knockout ESCs; neural differentiation assays; gene expression analysis The Journal of biological chemistry Medium 36764520
2018 Sox2 directly binds the Hes5 promoter (shown by ChIP in both PNS and CNS) and activates Hes5 expression; Sox2 conditional knockout in the olfactory epithelium reduces Hes5 induction and impairs neuronal progenitor maintenance and neurogenesis. ChIP for Sox2 at Hes5 promoter; Sox2 conditional knockout mice; CRISPR-Cas9 in chick; in situ hybridization; BrdU assays Development (Cambridge, England) High 29352015
2007 Hes5 negatively regulates contextual fear memory formation; SGK1 activation (via Ser78 phosphorylation) during fear training reduces Hes5 expression, and Hes5 knockdown by shRNA enhances fear retention while Hes5 overexpression impairs it; shHes5 blocks the memory-impairing effect of dominant-negative SGK. Dominant-negative and constitutively active SGK constructs transfected to hippocampal neurons; RNAi (shHes5); Hes5 overexpression; fear conditioning behavioral assay; microarray Journal of neurochemistry Medium 17241237
2019 DNA methylation of the Hes5 promoter CpG island silences Hes5 expression in SBMA motor neurons; DNA methyltransferase 1 (Dnmt1) is overexpressed in SBMA, and treatment with DNA methylation inhibitor RG108 restores Hes5 expression and ameliorates the SBMA phenotype; Hes5 overexpression rescues SBMA cells possibly by inducing Smad2 phosphorylation. DNA methylation array; bisulfite sequencing; Dnmt1 genetic depletion; RG108 treatment in vivo; Hes5 overexpression in SBMA cells; Western blot EMBO molecular medicine Medium 30940675
2008 Hey2 functions in parallel with Hes5 (and Hes1) in patterning the organ of Corti; genetic inactivation of Hey2 combined with loss of Hes5 leads to increased numbers of mis-patterned outer hair cells, demonstrating additive/parallel roles for these Notch target genes in auditory sensory organ patterning. Hey2/Hes5 double knockout mice; cochlear hair cell counting and patterning analysis BMC developmental biology Medium 18302773
2013 Hes1 and Hes5 are required for vascular remodeling and arterial identity specification in endothelial cells of the developing brain; endothelial-specific double mutant embryos show defective brain vascular remodeling and partial loss of arterial identity, establishing Hes1/Hes5 as critical Notch transducers in brain vascular development. Endothelial-specific conditional Hes1/Hes5 knockout mice; vascular morphology and arterial marker analysis Mechanisms of development Medium 23871867
2025 HES5+ astrocytes in the spinal dorsal horn enhance Aδ and C fiber-mediated excitatory postsynaptic currents in lamina I neurons; this synaptic potentiation requires NMDA receptor activity (specifically the glycine binding site), demonstrating a functional role for HES5-expressing astrocytes in nociceptive synaptic transmission. Chemogenetic stimulation of Hes5+ astrocytes; electrophysiological recordings; NMDA receptor pharmacological blockade; cell-type-specific functional manipulation Molecular brain Medium 40289116

Source papers

Stage 0 corpus · 65 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Hes1 and Hes5 as notch effectors in mammalian neuronal differentiation. The EMBO journal 698 10205173
2001 Roles of the basic helix-loop-helix genes Hes1 and Hes5 in expansion of neural stem cells of the developing brain. The Journal of biological chemistry 338 11399758
2001 Hes1 and Hes5 activities are required for the normal development of the hair cells in the mammalian inner ear. The Journal of neuroscience : the official journal of the Society for Neuroscience 244 11425898
2000 Glial cell fate specification modulated by the bHLH gene Hes5 in mouse retina. Development (Cambridge, England) 236 10821751
2007 Integrative genomic analyses on HES/HEY family: Notch-independent HES1, HES3 transcription in undifferentiated ES cells, and Notch-dependent HES1, HES5, HEY1, HEY2, HEYL transcription in fetal tissues, adult tissues, or cancer. International journal of oncology 132 17611704
2007 Identification of self-replicating multipotent progenitors in the embryonic nervous system by high Notch activity and Hes5 expression. The European journal of neuroscience 130 17331197
2000 Expression of Math1 and HES5 in the cochleae of wildtype and Jag2 mutant mice. Journal of the Association for Research in Otolaryngology : JARO 124 11545143
2003 Hes1 but not Hes5 regulates an astrocyte versus oligodendrocyte fate choice in glial restricted precursors. Developmental dynamics : an official publication of the American Association of Anatomists 103 12666205
1995 Structure and promoter analysis of the gene encoding the mouse helix-loop-helix factor HES-5. Identification of the neural precursor cell-specific promoter element. The Journal of biological chemistry 98 7836401
2005 A novel hes5/hes6 circuitry of negative regulation controls Notch activity during neurogenesis. Developmental biology 94 15893982
2004 Identification and characterization of human HES2, HES3, and HES5 genes in silico. International journal of oncology 85 15254753
2017 Hes5 regulates the transition timing of neurogenesis and gliogenesis in mammalian neocortical development. Development (Cambridge, England) 81 28851724
2004 Expression of Hairy/Enhancer of Split genes, Hes1 and Hes5, during murine nephron morphogenesis. Gene expression patterns : GEP 71 15465493
2010 Zinc finger genes Fezf1 and Fezf2 control neuronal differentiation by repressing Hes5 expression in the forebrain. Development (Cambridge, England) 67 20431123
2008 Notch1, Jagged1, and HES5 are abundantly expressed in osteoarthritis. Cells, tissues, organs 66 18354251
2012 Sox21 promotes hippocampal adult neurogenesis via the transcriptional repression of the Hes5 gene. The Journal of neuroscience : the official journal of the Society for Neuroscience 60 22956844
2008 Hey2 functions in parallel with Hes1 and Hes5 for mammalian auditory sensory organ development. BMC developmental biology 58 18302773
2009 Hes5 expression in the postnatal and adult mouse inner ear and the drug-damaged cochlea. Journal of the Association for Research in Otolaryngology : JARO 57 19373512
2011 Mammalian Gcm genes induce Hes5 expression by active DNA demethylation and induce neural stem cells. Nature neuroscience 55 21765423
2019 Quantitative single-cell live imaging links HES5 dynamics with cell-state and fate in murine neurogenesis. Nature communications 49 31249377
2013 Fbw7 repression by hes5 creates a feedback loop that modulates Notch-mediated intestinal and neural stem cell fate decisions. PLoS biology 48 23776410
2008 Cdc42-mTOR signaling pathway controls Hes5 and Pax6 expression in retinoic acid-dependent neural differentiation. The Journal of biological chemistry 48 19097998
2006 Notch and HES5 are regulated during human cartilage differentiation. Cell and tissue research 48 17093926
2013 Hes1 and Hes5 regulate vascular remodeling and arterial specification of endothelial cells in brain vascular development. Mechanisms of development 46 23871867
2002 Notch/Notch ligands and Math1 expression patterns in the organ of Corti of wild-type and Hes1 and Hes5 mutant mice. Hearing research 45 12208538
2020 NOTCH target gene HES5 mediates oncogenic and tumor suppressive functions in hepatocarcinogenesis. Oncogene 36 32055024
2013 siRNA targeting Hes5 augments hair cell regeneration in aminoglycoside-damaged mouse utricle. Molecular therapy : the journal of the American Society of Gene Therapy 35 23439501
2013 Regeneration of mammalian cochlear and vestibular hair cells through Hes1/Hes5 modulation with siRNA. Hearing research 33 23850665
2018 SOX4 inhibits oligodendrocyte differentiation of embryonic neural stem cells in vitro by inducing Hes5 expression. Stem cell research 32 30343100
2007 Serum- and glucocorticoid-inducible kinase1 enhances contextual fear memory formation through down-regulation of the expression of Hes5. Journal of neurochemistry 30 17241237
2018 Sox2 is required for olfactory pit formation and olfactory neurogenesis through BMP restriction and Hes5 upregulation. Development (Cambridge, England) 29 29352015
2005 Changes in the expression of Hes5 and Mash1 mRNA in the adult rat dentate gyrus after transient forebrain ischemia. Neuroscience letters 26 15854743
2014 Control of hair cell development by molecular pathways involving Atoh1, Hes1 and Hes5. Gene 25 25550047
2023 Notch3/Hes5 Induces Vascular Dysfunction in Hypoxia-Induced Pulmonary Hypertension Through ER Stress and Redox-Sensitive Pathways. Hypertension (Dallas, Tex. : 1979) 24 37254738
2014 HES5 is a key mediator of Wnt-3a-induced neuronal differentiation. Stem cells and development 23 24548083
2014 Increased expression of Hes5 protein in Notch signaling pathway in the hippocampus of mice offspring of dams fed a high-fat diet during pregnancy and suckling. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 23 25450527
2010 Hes1/Hes5 gene inhibits differentiation via down-regulating Hash1 and promotes proliferation in cervical carcinoma cells. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 19 21495212
2007 Expression of differentiation associated protein Hes1 and Hes5 in cervical squamous carcinoma and its precursors. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 19 17388915
2021 A dynamic, spatially periodic, micro-pattern of HES5 underlies neurogenesis in the mouse spinal cord. Molecular systems biology 18 34031978
2017 Separate and coincident expression of Hes1 and Hes5 in the developing mouse eye. Developmental dynamics : an official publication of the American Association of Anatomists 17 28675662
2007 Notch target Hes5 ensures appropriate Notch induced T- versus B-cell choices in the thymus. Blood 17 18048645
2019 DNA methylation inhibitor attenuates polyglutamine-induced neurodegeneration by regulating Hes5. EMBO molecular medicine 16 30940675
2021 Repression of FBXW7 by HES5 contributes to inactivation of the TGF-β signaling pathway and alleviation of endometriosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 14 33496006
2018 Targeted delivery of HES5-siRNA with novel polypeptide-modified nanoparticles for hepatocellular carcinoma therapy. RSC advances 12 35542585
2010 HES1 and HES5 are dispensable for cartilage and endochondral bone formation. Cells, tissues, organs 12 20134146
2023 Transcription factor SOX15 regulates stem cell pluripotency and promotes neural fate during differentiation by activating the neurogenic gene Hes5. The Journal of biological chemistry 11 36764520
2015 HES5 silencing is an early and recurrent change in prostate tumourigenesis. Endocrine-related cancer 11 25560400
2006 Expression of Notch1 and Hes5 in the developing olfactory epithelium. Acta oto-laryngologica 8 16698699
2020 Synaptic remodeling and reduced expression of the transcription factors, HES1 and HES5, in the cortex neurons of cognitively impaired hyperhomocysteinemic mice. Pathology, research and practice 7 32345540
2004 Possible role of Hes5 for the rostrocaudal polarity formation of the tectum. Development, growth & differentiation 7 15206953
2017 Transient HES5 Activity Instructs Mesodermal Cells toward a Cardiac Fate. Stem cell reports 6 28648899
2021 Evolution of hes gene family in vertebrates: the hes5 cluster genes have specifically increased in frogs. BMC ecology and evolution 5 34325655
2018 Hyperhomocysteinemia induces injury in olfactory bulb neurons by downregulating Hes1 and Hes5 expression. Neural regeneration research 5 29557377
2016 HES5 promotes cellular proliferation of non-small cell lung cancer through STAT3 signaling. Oncology reports 5 27878283
2021 HES5 Activates Long Noncoding RNA UCA1 to Induce Colorectal Cancer Progression by Modulating miR-185/NOTCH3 Signaling. Gastroenterology research and practice 4 34733326
2019 Exploration of the Notch3-HES5 signal pathway in monocrotaline-induced pulmonary hypertension using rat model. Congenital heart disease 3 30811836
2020 Hes5.9 Coordinate FGF and Notch Signaling to Modulate Gastrulation via Regulating Cell Fate Specification and Cell Migration in Xenopus tropicalis. Genes 2 33218193
2025 Hes5+ astrocytes potentiate primary afferent Aδ and C fiber-mediated excitatory synaptic transmission to spinal lamina I neurons. Molecular brain 1 40289116
2025 Androgen receptor inhibitor ameliorates pulmonary arterial hypertension by enhancing the apoptosis level through suppressing the Notch3/Hes5 pathway. Frontiers in pharmacology 1 40356960
2025 PCSK9 Loss-of-Function Disrupts Cellular Microfilament Network via LIN28A/HES5/JMY Axis in Neural Tube Defects. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 1 40788992
2026 Salidroside targets the Notch1/Hes5 axis to reconstruct the molecular innate immune-vascular network and correlates with repair after ischemic stroke. Frontiers in immunology 0 41756274
2025 Low SVEP1 in intrahepatic cholangiocarcinoma mediates phenotype switching-driven metastasis by Jag2/Notch1/Hes5. Cell death & disease 0 41315239
2024 Comparative Analysis of Transcription Factors TWIST2, GATA3, and HES5 in Glioblastoma Multiforme : Evaluating Biomarker Potential and Therapeutic Targets Using in Silico Methods. Journal of Korean Neurosurgical Society 0 39444320
2021 HES5-mediated repression of LIGHT transcription may contribute to apoptosis in hepatocytes. Cell death discovery 0 34689159
2004 [Blocking with double- stranded RNA of the expression of Hes5 in rat bone marrow-derived neural stem cells]. Di 1 jun yi da xue xue bao = Academic journal of the first medical college of PLA 0 14724091