Affinage

HESX1

Homeobox expressed in ES cells 1 · UniProt Q9UBX0

Length
185 aa
Mass
21.4 kDa
Annotated
2026-06-10
100 papers in source corpus 20 papers cited in narrative 20 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HESX1 is a homeodomain transcriptional repressor that enforces anterior neural identity and pituitary organogenesis during early development, where it is required cell-autonomously within the anterior neural ectoderm for forebrain formation (PMID:10882526, PMID:17360769). It binds dimeric homeodomain DNA sites with high affinity through its homeodomain, and mutations that abolish or weaken this binding (R160C, S170L) cause forebrain, midline, and pituitary defects; R160C additionally acts as a dominant negative by sequestering wild-type protein (PMID:9620767, PMID:11748154, PMID:11136712, PMID:19093031). Repression is executed through a 36-amino-acid Engrailed-homology (eh1) domain that recruits the Groucho-related corepressors TLE1 and TLE3, and an eh1 point mutation (I26T) abolishes TLE1 recruitment and produces a hypomorphic allele in vivo (PMID:14561704, PMID:19093031, PMID:20181723). In the forebrain, HESX1 antagonizes Wnt/β-catenin signalling to prevent posterior transformation of anterior tissue, acting synergistically with the Wnt repressor TCF3, and conditional removal of β-catenin rescues the Hesx1-null forebrain (PMID:17360769, PMID:22007134). In the pituitary it antagonizes PROP1-mediated activation, and its own expression must be extinguished to permit lineage-specific proliferation, as shown by genetic epistasis with the Ames dwarf locus and Six3 (PMID:8961267, PMID:18775421, PMID:27000987). HESX1 transcription is directly activated by OTX2 and by the LIM-homeodomain proteins Lhx1 and Lhx3, and repressed by Pax6 (PMID:15110720, PMID:16527264, PMID:18628516). It also physically interacts with DNMT1 and, via its ortholog Xanf1, with Zyxin, extending the repertoire of its repressive mechanisms (PMID:17931718, PMID:18297730).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1995 Medium

    Established HESX1/Rpx as a novel-class homeodomain protein whose expression marks early developmental decisions, defining the molecule before its function was known.

    Evidence Molecular cloning, sequencing, and expression profiling in differentiating ES cells

    PMID:7876132

    Open questions at the time
    • No functional or phenotypic data
    • DNA-binding specificity not yet defined
  2. 1996 High

    Placed Rpx/Hesx1 repression upstream of Pit1 in pituitary ontogeny, showing that its extinction is a prerequisite for lineage-specific proliferation.

    Evidence Double-mutant epistasis (Ames df and Pit1-dw mice) with in situ hybridization and cell-size measurement

    PMID:8961267

    Open questions at the time
    • Molecular identity of the df gene unresolved here
    • Direct transcriptional targets not identified
  3. 1998 High

    Demonstrated that DNA binding by HESX1 is required for forebrain, midline, and pituitary development by linking a homeodomain missense mutation that abolishes binding to disease and recapitulating defects in knockout mice.

    Evidence EMSA of mutant protein plus targeted knockout in mice with phenotypic analysis

    PMID:9620767

    Open questions at the time
    • Target genes bound in vivo not defined
    • Repression mechanism not yet established
  4. 2000 High

    Resolved the tissue of action, showing HESX1 is required cell-autonomously in the anterior neural ectoderm rather than visceral endoderm for forebrain formation.

    Evidence Reciprocal chimeric embryo analysis with marker in situ hybridization (Six3, Rax)

    PMID:10882526

    Open questions at the time
    • Direct vs indirect regulation of Six3/Rax not distinguished
    • Signalling pathway antagonized not identified
  5. 2001 High

    Defined HESX1 as a promoter-specific repressor with a minimal 36-residue repression domain and quantified how disease mutations alter DNA binding, including a dominant-negative mechanism.

    Evidence Quantitative EMSA with purified proteins, luciferase reporter assays, deletion mutagenesis (with allele-specific EMSA in a parallel study)

    PMID:11136712 PMID:11748154

    Open questions at the time
    • Corepressor recruited by the repression domain not yet identified
    • Physiological target promoters unknown
  6. 2003 High

    Identified the eh1 domain as the corepressor-recruitment module by showing an I26T mutation preserves DNA binding but abolishes TLE1/Groucho recruitment, and documented a gain-of-repressor mechanism for pituitary disease.

    Evidence Co-IP of HESX1 and TLE1, reporter repression assays, and EMSA; separate reporter/EMSA study of a frameshift gain-of-function allele

    PMID:14557462 PMID:14561704

    Open questions at the time
    • Whether TLE recruitment occurs at endogenous promoters not shown
    • In vivo consequence of I26T not yet tested at this stage
  7. 2004 Medium

    Connected HESX1 to its upstream regulatory network by showing Otx2 directly activates and Pax6 directly represses the promoter.

    Evidence In vivo site mutagenesis in transgenic chick/zebrafish, occupancy analysis, and Pax6-null marker analysis

    PMID:15110720

    Open questions at the time
    • Combinatorial logic of activators and repressors not resolved
    • Single lab
  8. 2006 Medium

    Extended the upstream network by mapping distinct enhancers and showing LIM-homeodomain proteins Lhx1 and Lhx3 directly bind and drive early Rpx transcription.

    Evidence Transgenic reporter deletion analysis and EMSA in mouse and Xenopus

    PMID:16527264

    Open questions at the time
    • Functional requirement of Lhx binding in vivo not tested by knockout
    • 3' Rathke's pouch enhancer regulators not identified
  9. 2007 High

    Established the core developmental mechanism: HESX1 represses Wnt/β-catenin signalling to prevent posterior transformation of anterior forebrain, and identified DNMT1 as a physical partner.

    Evidence Conditional β-catenin deletion in Hesx1-null background (rescue) with profiling; yeast two-hybrid, co-IP, and co-localization for DNMT1

    PMID:17360769 PMID:17931718

    Open questions at the time
    • Direct Wnt target promoters bound by HESX1 not enumerated
    • Functional consequence of DNMT1 interaction not demonstrated
  10. 2008 High

    Validated the allelic series in vivo (I26T hypomorph, R160C null), revealed genetic interaction with Six3 in pituitary proliferation, identified Zyxin as a negative modulator of the ortholog, and confirmed OTX2 directly transactivates the HESX1 promoter.

    Evidence Two knock-in mouse lines; Six3;Hesx1 compound heterozygote analysis; Xenopus Xanf1–Zyxin pulldown and gain/loss-of-function; OTX2 reporter assay

    PMID:18297730 PMID:18628516 PMID:18775421 PMID:19093031

    Open questions at the time
    • Mechanism by which Six3 dosage controls pouch proliferation unresolved
    • Zyxin modulation shown only in Xenopus ortholog
  11. 2010 High

    Broadened the corepressor mechanism by showing HESX1 recruits both TLE1 and TLE3 to repress PROP1-dependent transcription, with TLE corepressors augmenting repression in vivo.

    Evidence Reciprocal co-IP, reporter assays, and transgenic pituitary overexpression with differentiation readout

    PMID:20181723

    Open questions at the time
    • Endogenous PROP1 target genes co-repressed not mapped
    • Relative contribution of TLE1 vs TLE3 in vivo unclear
  12. 2011 High

    Demonstrated that HESX1 and TCF3 act synergistically to repress Wnt targets and maintain anterior forebrain identity across species.

    Evidence Double-mutant mouse epistasis, zebrafish morpholino knockdown in tcf3 background, conditional knockout, and transcriptional profiling

    PMID:22007134

    Open questions at the time
    • Whether HESX1 and TCF3 co-occupy shared promoters not shown directly
    • Specific Wnt target genes repressed not fully enumerated
  13. 2016 Medium

    Confirmed that conserved homeodomain residues R159 and R160 are individually required for repression of PROP1, refining genotype-phenotype relationships.

    Evidence Luciferase reporter repression assay with compound-heterozygous mutant proteins

    PMID:27000987

    Open questions at the time
    • DNA-binding consequences of these residues not assayed here
    • Single method, single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • The genome-wide direct target repertoire of HESX1 and how its DNMT1 interaction contributes to repression at endogenous loci remain undefined.
  • No ChIP-based genome-wide occupancy map
  • Functional role of HESX1–DNMT1 in DNA methylation untested
  • Structural model of the homeodomain on dimeric sites lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 4 GO:0140110 transcription regulator activity 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-162582 Signal Transduction 2
Partners
DNMT1LHX1LHX3OTX2PROP1TCF3TLE1TLE3

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 A homozygous Arg53Cys missense mutation within the HESX1 homeodomain destroyed its ability to bind target DNA, establishing that DNA binding by HESX1 is required for normal forebrain, midline, and pituitary development. Mouse knockouts lacking Hesx1 showed variable anterior CNS defects and pituitary dysplasia. Gel shift (EMSA) DNA-binding assay of mutant protein; targeted gene knockout in mice with phenotypic analysis Nature genetics High 9620767
1995 Hesx1 (Rpx) is expressed as two transcripts encoding an identical 185-amino-acid homeodomain protein that defines a new homeodomain class (sharing 80% identity with Xenopus XANF-1). Expression is down-regulated during ES cell differentiation, consistent with a role in early developmental decisions. Molecular cloning, sequencing, Northern blot, and tissue-specific expression analysis from embryonic stem cells The Journal of biological chemistry Medium 7876132
1996 In the Ames dwarf (df) mouse, the df gene acts upstream of Pit1 in pituitary ontogeny: df mutants fail to extinguish Rpx/Hesx1 transcription by e13.5, and the pituitary is hypocellular, whereas Pit1-mutant pituitaries down-regulate Rpx normally. This genetic epistasis places Rpx repression as a prerequisite for lineage-specific cell proliferation. Genetic epistasis analysis in double-mutant mice (df and Pit1-dw); RNA in situ hybridization; pituitary cell-size measurements Molecular endocrinology (Baltimore, Md.) High 8961267
2000 Hesx1 is required cell-autonomously within the anterior neural ectoderm (ANE) for normal forebrain formation. Chimeric analysis showed that Hesx1-deficient visceral endoderm does not cause forebrain defects, but Hesx1-null cells in the ANE do. Downstream ANE markers Six3 and Rax/Rx are normally expressed until the early somite stage but become markedly reduced ~24 h after Hesx1 is first expressed in the ANE. Chimeric embryo analysis (ES cell injection into wild-type blastocysts and reciprocal); RNA in situ hybridization for tissue markers Developmental biology High 10882526
2001 HESX1 is a promoter-specific transcriptional repressor with a minimal 36-amino-acid repression domain. It suppresses homeodomain-containing activator proteins. Wild-type HESX1 binds a dimeric homeodomain site with high affinity (Kd ~31 nM); HESX1-S170L binds with ~5-fold lower affinity (Kd ~150 nM); HESX1-R160C does not bind DNA at all. HESX1-R160C also acts as a dominant negative by inhibiting wild-type HESX1 DNA binding both in vitro and in cell culture, via its repression domain. Electrophoretic mobility shift assay (EMSA) with purified proteins; luciferase reporter transcription assays in cell culture; deletion mutagenesis defining the repression domain Development (Cambridge, England) High 11748154
2001 Gel shift analysis of the HESX1-S170L mutant protein showed a significant reduction in relative DNA-binding activity, linking this heterozygous mutation to sporadic pituitary hypoplasia. Gel shift (EMSA) assay of mutant HESX1 protein Human molecular genetics Medium 11136712
2003 A homozygous I26T mutation in the Engrailed homology 1 (eh1) repressor domain of HESX1 does not affect DNA binding but abolishes recruitment of the Groucho homologue/TLE1 corepressor, leading to partial loss of transcriptional repression. This demonstrates that the eh1 domain is required for HESX1–TLE1 interaction and full repressor activity. In vitro binding assays (co-immunoprecipitation of HESX1 and TLE1); transcriptional repression assays in cell culture with wild-type and I26T mutant HESX1; EMSA for DNA binding The Journal of clinical investigation High 14561704
2003 A novel HESX1 mutation (g.1684delG) generates a mutant protein with increased DNA-binding activity, causing enhanced repression of PROP1-dependent gene activity. This demonstrates that gain-of-repressor function is a mechanism for congenital pituitary disorders, distinct from previously described loss-of-function mutations. Luciferase reporter transcriptional repression assays; EMSA DNA-binding assays with mutant HESX1 protein The Journal of clinical endocrinology and metabolism Medium 14557462
2006 Two novel homozygous HESX1 mutations (a frameshift c.449_450delAC and a splice defect c.357+2T>C) produce truncated proteins lacking part or all of the homeodomain, with complete loss of transcriptional repressor activity as demonstrated by inability to inhibit PROP1 activity in reporter assays. Sequencing of HESX1 exons; RT-PCR analysis of transcripts from splice mutant; luciferase-based transcriptional repression assay The Journal of clinical endocrinology and metabolism Medium 16940453
2007 Hesx1 functions as an essential repressor in the anterior forebrain; its absence leads to a posterior transformation of the anterior forebrain via ectopic activation of Wnt/β-catenin signalling within the Hesx1 expression domain. Conditional deletion of β-catenin in the anterior forebrain of Hesx1-deficient embryos significantly rescues the forebrain defects. Genetic cell labelling; marker gene analysis; conditional knockout of β-catenin in Hesx1-null background (double mutant rescue); transcriptional profiling of anterior forebrain precursors Development (Cambridge, England) High 17360769
2007 DNMT1 (DNA methyltransferase 1) is a binding partner of HESX1. The entire HESX1 protein is required for binding to the N-terminus and catalytic C-terminal domain of DNMT1. HESX1–DNMT1 complexes co-immunoprecipitate in cells and co-localise in the nucleus; Dnmt1 and Hesx1 are co-expressed in anterior forebrain and Rathke's pouch. Yeast two-hybrid screen; co-immunoprecipitation; deletion-mutant binding mapping; co-localisation by immunofluorescence in cells Biochimica et biophysica acta Medium 17931718
2008 Knock-in mice carrying the I26T substitution in Hesx1 show pituitary defects comparable to Hesx1-null mice, confirming I26T as a hypomorphic allele. Knock-in mice carrying R160C show full forebrain and pituitary defects identical to null mice, confirming R160C is a null allele. HESX1 expression during early human development mirrors the mouse, supporting conservation of function. Generation of two Hesx1 knock-in mouse lines (I26T and R160C) by gene targeting; histological and molecular phenotypic analysis; immunohistochemistry in human embryos Disease models & mechanisms High 19093031
2008 Hesx1 interacts genetically with Six3 during pituitary development: Six3+/-;Hesx1Cre/+ compound heterozygous mice display severe pituitary hypoplasia with an expanded/bifurcated Rathke's pouch due to increased cell proliferation, revealing a genetic interaction between Hesx1 and Six3 in controlling pituitary organogenesis. Generation of Six3+/-;Hesx1Cre/+ double-heterozygous mice; histological and proliferation analyses; endocrine phenotype assessment Developmental biology High 18775421
2008 The Xenopus/Hesx1 ortholog Xanf1 binds the LIM-domain protein Zyxin through its Engrailed-type repressor domain (eh1), and Zyxin LIM2 domain is required for the interaction. Zyxin overexpression mimics Xanf1 knockdown, while a repressor-fused Zyxin mimics Xanf1 overexpression, indicating Zyxin acts as a negative modulator of Xanf1 transcriptional repressing activity in the anterior neural plate. Deletion-mutant pulldown mapping; Xenopus embryo overexpression and morpholino knockdown with phenotypic readout Developmental dynamics Medium 18297730
2010 HESX1 interacts with both TLE1 and TLE3 corepressors to repress PROP1-dependent transcription. TLE3 had not previously been shown to interact with HESX1. In transgenic mice, HESX1 alone (but not TLE3 alone) suppresses terminal differentiation of thyrotrophs and gonadotrophs when constitutively expressed, and TLE3 together with HESX1 shows similar suppression, demonstrating that TLE corepressors augment HESX1-mediated repression. Cell-based luciferase reporter assays; co-immunoprecipitation; transgenic mouse overexpression in pituitary thyrotrophs/gonadotrophs with cell differentiation readout Molecular endocrinology (Baltimore, Md.) High 20181723
2011 HESX1 and TCF3 (a transcriptional repressor of Wnt target genes) act synergistically to maintain anterior forebrain identity by repressing Wnt/β-catenin targets. Hesx1/Tcf3 double-heterozygous mice show severe forebrain defects not seen in single heterozygotes. Morpholino knockdown of hesx1 in tcf3-mutant zebrafish causes severe forebrain and eye defects. Tcf3 conditional knockout in the neural ectoderm causes anterior forebrain loss, and Tcf3/Hesx1 compound deficiency amplifies this. Transcriptional profiling of Hesx1-expressing forebrain precursors provides molecular evidence for Wnt target repression. Double-mutant mouse epistasis; zebrafish morpholino knockdown in sensitised tcf3 mutant background; conditional knockout; transcriptional profiling (gene expression array) Development (Cambridge, England) High 22007134
2004 The HESX1/ANF homeobox gene promoter is directly activated by Otx2 through two conserved Otx2-binding sites in a ~1-kb upstream enhancer, as shown by in vivo mutagenesis in chick and zebrafish transgenic embryos. Additionally, Pax6 occupies a binding site near the transcriptional start site in vivo and inhibits GANF/Hesx1 expression: Pax6 overexpression represses endogenous GANF, and in Pax6-null mice the Hesx1 expression domain is expanded and prolonged. In vivo site mutagenesis in transgenic chick and zebrafish; chromatin/in vivo occupancy analysis; Pax6-null mouse marker analysis; overexpression experiments Developmental biology Medium 15110720
2006 Conserved 5′ upstream regulatory sequences of Rpx/Hesx1 contain two LIM protein-binding sites that are required for Rpx promoter activity and are directly bound by LIM homeodomain proteins Lhx1 and Lhx3, which regulate early Rpx transcription in the anterior endoderm and neural plate. A conserved 3′ enhancer is necessary and sufficient for Rpx expression in Rathke's pouch. Transgenic mouse reporter analysis with deletion constructs; electrophoretic mobility shift assay (EMSA) for Lhx1 and Lhx3 binding; Xenopus transgenic assay Developmental biology Medium 16527264
2008 Wild-type OTX2 protein binds to the HESX1 promoter and transactivates it ~4.5-fold. A frameshift OTX2 mutation that retains the homeodomain but loses the transactivation domain fails to transactivate the HESX1 promoter, establishing HESX1 as a direct transcriptional target of OTX2 in the pituitary context. Luciferase reporter assay with wild-type and mutant OTX2; nuclear localisation confirmed by imaging The Journal of clinical endocrinology and metabolism Medium 18628516
2016 Compound heterozygous HESX1 mutations p.R159W and p.R160H each abrogate the ability of HESX1 to repress PROP1-mediated transcriptional activation, demonstrating that both residues are required for HESX1 repressor function toward PROP1. Luciferase reporter transcriptional repression assay with mutant HESX1 proteins Clinical endocrinology Medium 27000987

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nature genetics 513 9620767
2002 Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expression in the atrioventricular canal: implications for cardiac chamber formation. Genes & development 292 12023302
1996 Rpx: a novel anterior-restricted homeobox gene progressively activated in the prechordal plate, anterior neural plate and Rathke's pouch of the mouse embryo. Development (Cambridge, England) 245 8565852
2001 Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Human molecular genetics 208 11136712
1986 Myocardial recruitment during ANF mRNA increase with volume overload in the rat. The American journal of physiology 204 2430471
1996 The Ames dwarf gene, df, is required early in pituitary ontogeny for the extinction of Rpx transcription and initiation of lineage-specific cell proliferation. Molecular endocrinology (Baltimore, Md.) 138 8961267
2006 HESX1 mutations are an uncommon cause of septooptic dysplasia and hypopituitarism. The Journal of clinical endocrinology and metabolism 104 17148560
2001 Molecular effects of novel mutations in Hesx1/HESX1 associated with human pituitary disorders. Development (Cambridge, England) 104 11748154
2003 A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction. The Journal of clinical investigation 103 14561704
2005 Hey basic helix-loop-helix transcription factors are repressors of GATA4 and GATA6 and restrict expression of the GATA target gene ANF in fetal hearts. Molecular and cellular biology 98 16199874
1995 Sequence, genomic organization, and expression of the novel homeobox gene Hesx1. The Journal of biological chemistry 93 7876132
2000 The homeobox gene Hesx1 is required in the anterior neural ectoderm for normal forebrain formation. Developmental biology 91 10882526
2003 Sporadic heterozygous frameshift mutation of HESX1 causing pituitary and optic nerve hypoplasia and combined pituitary hormone deficiency in a Japanese patient. The Journal of clinical endocrinology and metabolism 88 12519827
1998 ANF elicits phosphorylation of the cGMP phosphodiesterase in vascular smooth muscle cells. The American journal of physiology 85 9486247
1995 Divergent pathways mediate the induction of ANF transgenes in neonatal and hypertrophic ventricular myocardium. The Journal of clinical investigation 84 7657806
2003 Transgenic analysis of the atrialnatriuretic factor (ANF) promoter: Nkx2-5 and GATA-4 binding sites are required for atrial specific expression of ANF. Developmental biology 79 12941624
1992 Neurohormonal inhibition and hemodynamic unloading during prolonged inhibition of ANF degradation in patients with severe chronic heart failure. Circulation 79 1394917
1989 UK-69,578, a novel inhibitor of EC 3.4.24.11 which increases endogenous ANF levels and is natriuretic and diuretic. Biochemical and biophysical research communications 78 2529858
1986 Mechanisms of release of atrial natriuretic factor. II. Effect of chronic administration of alpha- and beta-adrenergic and cholinergic agonists on plasma and atrial ANF in the rat. Biochemical and biophysical research communications 78 2871836
1985 Structure-activity relationships of atrial natriuretic factor (ANF). II. Effect of chain-length modifications on vascular reactivity. Biochemical and biophysical research communications 78 4038600
2007 Lack of the murine homeobox gene Hesx1 leads to a posterior transformation of the anterior forebrain. Development (Cambridge, England) 68 17360769
1994 Classical, novel and atypical isoforms of PKC stimulate ANF- and TRE/AP-1-regulated-promoter activity in ventricular cardiomyocytes. FEBS letters 68 7805853
1991 Influence of C-ANF receptor and neutral endopeptidase on pharmacokinetics of ANF in rats. The American journal of physiology 66 1847022
1987 Divergence of ANF analogs in smooth muscle cell cGMP response and aorta vasorelaxation: evidence for receptor subtypes. Biochemical and biophysical research communications 66 3034249
2005 Mutation analysis of POUF-1, PROP-1 and HESX-1 show low frequency of mutations in children with sporadic forms of combined pituitary hormone deficiency and septo-optic dysplasia. Clinical endocrinology 63 15670191
1991 Kidney function in ANF-transgenic mice: effect of blood volume expansion. The American journal of physiology 62 1825155
2003 Enhanced repression by HESX1 as a cause of hypopituitarism and septooptic dysplasia. The Journal of clinical endocrinology and metabolism 61 14557462
1988 Glomerular ANF receptor regulation during changes in sodium and water metabolism. The American journal of physiology 59 2827518
2008 OTX2 mutation in a patient with anophthalmia, short stature, and partial growth hormone deficiency: functional studies using the IRBP, HESX1, and POU1F1 promoters. The Journal of clinical endocrinology and metabolism 58 18628516
2006 Novel HESX1 mutations associated with a life-threatening neonatal phenotype, pituitary aplasia, but normally located posterior pituitary and no optic nerve abnormalities. The Journal of clinical endocrinology and metabolism 58 16940453
2008 Genetic interaction between the homeobox transcription factors HESX1 and SIX3 is required for normal pituitary development. Developmental biology 51 18775421
2001 Regulation of the ANF and BNP promoters by GATA factors: lessons learned for cardiac transcription. Canadian journal of physiology and pharmacology 51 11558676
1990 Degradation and clearance of atrial natriuretic factors (ANF). Life sciences 50 2173807
1989 Urodilatin and beta-ANF: binding properties and activation of particulate guanylate cyclase. Biochemical and biophysical research communications 50 2570574
2000 The Rho effector, PKN, regulates ANF gene transcription in cardiomyocytes through a serum response element. American journal of physiology. Heart and circulatory physiology 49 10843871
1986 ANF stimulation of detergent-dispersed particulate guanylate cyclase from bovine adrenal cortex. FEBS letters 49 2866981
1976 Cooperative control of translational fidelity by ribosomal proteins in Escherichia coli. III. A ram mutation in the structural gene for protein S5 (rpx E). Molecular & general genetics : MGG 48 772415
2013 A transgenic mouse model for the simultaneous monitoring of ANF and BNP gene activity during heart development and disease. Cardiovascular research 46 24104878
1996 Influence of fibroblast growth factor (bFGF) and insulin-like growth factor (IGF-I) on cytoskeletal and contractile structures and on atrial natriuretic factor (ANF) expression in adult rat ventricular cardiomyocytes in culture. Journal of molecular and cellular cardiology 45 8745211
1991 RT-PCR microlocalization of mRNA for guanylyl cyclase-coupled ANF receptor in rat kidney. The American journal of physiology 43 1721496
2011 HESX1- and TCF3-mediated repression of Wnt/β-catenin targets is required for normal development of the anterior forebrain. Development (Cambridge, England) 42 22007134
2004 Involvement of Pax6 and Otx2 in the forebrain-specific regulation of the vertebrate homeobox gene ANF/Hesx1. Developmental biology 42 15110720
1995 Atrial natriuretic factor modulates nitric oxide production: an ANF-C receptor-mediated effect. Journal of hypertension 39 7594419
1994 ANF-C-receptor-mediated inhibition of aortic smooth muscle cell proliferation and thymidine kinase activity. The American journal of physiology 39 8304541
1992 Captopril enhances renal responsiveness to ANF in dogs with compensated high-output heart failure. The American journal of physiology 39 1313653
1988 ANF receptors: distribution and regulation in central and peripheral tissues. Neuroscience and biobehavioral reviews 39 2845313
1995 Heterogeneity within human-derived centers for disease control and prevention (CDC) coryneform group ANF-1-like bacteria and description of Corynebacterium auris sp. nov. International journal of systematic bacteriology 37 7547292
1993 Phenylephrine and endothelin differentially stimulate cardiac PI hydrolysis and ANF expression. The American journal of physiology 37 8383460
2008 Analysis of mouse models carrying the I26T and R160C substitutions in the transcriptional repressor HESX1 as models for septo-optic dysplasia and hypopituitarism. Disease models & mechanisms 35 19093031
2007 Hormonal, pituitary magnetic resonance, LHX4 and HESX1 evaluation in patients with hypopituitarism and ectopic posterior pituitary lobe. Clinical endocrinology 35 17201807
2003 Clinical characteristics and molecular analysis of PIT1, PROP1,LHX3, and HESX1 in combined pituitary hormone deficiency patients with abnormal pituitary MR imaging. Hormone research 34 14646405
1993 Taxonomic study of Corynebacterium Group ANF-1 strains: Proposal of Corynebacterium afermentans sp. nov. containing the subspecies C. afermentans subsp. afermentans subsp. nov. and C. afermentans subsp. lipophilum subsp. nov. International journal of systematic bacteriology 34 8494739
2000 Dopamine induces a biphasic modulation of hypothalamic ANF neurons: a ligand concentration-dependent effect involving D5 and D2 receptor interaction. Molecular psychiatry 33 10673767
1994 Losartan improves the natriuretic response to ANF in rats with high-output heart failure. The Journal of pharmacology and experimental therapeutics 33 8301562
1993 Immunocytochemical localization of atrial natriuretic factor (ANF)-like peptides in the brain and heart of the treefrog Hyla japonica: effect of weightlessness on the distribution of immunoreactive neurons and cardiocytes. The Journal of comparative neurology 33 8468402
2010 PROP1, HESX1, POU1F1, LHX3 and LHX4 mutation and deletion screening and GH1 P89L and IVS3+1/+2 mutation screening in a Dutch nationwide cohort of patients with combined pituitary hormone deficiency. Hormone research in paediatrics 32 20389107
2007 Molecular analysis of PROP1, PIT1, HESX1, LHX3, and LHX4 shows high frequency of PROP1 mutations in patients with familial forms of combined pituitary hormone deficiency. Arquivos brasileiros de endocrinologia e metabologia 32 18157385
1992 Role of spleen in ANF-induced reduction in plasma volume. Canadian journal of physiology and pharmacology 32 1473042
1991 Cellular signals regulating the release of ANF. Canadian journal of physiology and pharmacology 32 1838021
2009 beta-Catenin/TCF/LEF1 can directly regulate phenylephrine-induced cell hypertrophy and Anf transcription in cardiomyocytes. Biochemical and biophysical research communications 31 19799869
1995 Blood pressure and fluid-electrolyte balance in ANF-transgenic mice on high- and low-salt diets. The American journal of physiology 31 7631892
1988 Involvement of Ni protein in the functional coupling of the atrial natriuretic factor (ANF) receptor to adenylate cyclase in rat lung plasma membranes. European journal of biochemistry 31 2839333
2011 GATA4 regulates ANF expression synergistically with Sp1 in a cardiac hypertrophy model. Journal of cellular and molecular medicine 29 20874724
1992 Pharmacokinetics of ANF and urodilatin during cANF receptor blockade and neutral endopeptidase inhibition. The American journal of physiology 27 1443119
2008 The LIM-domain protein Zyxin binds the homeodomain factor Xanf1/Hesx1 and modulates its activity in the anterior neural plate of Xenopus laevis embryo. Developmental dynamics : an official publication of the American Association of Anatomists 26 18297730
2004 Transforming growth factor-beta induces the expression of ANF and hypertrophic growth in cultured cardiomyoblast cells through ZAK. Biochemical and biophysical research communications 26 15465036
1995 C-type natriuretic peptide and brain natriuretic peptide inhibit adenylyl cyclase activity: interaction with ANF-R2/ANP-C receptors. FEBS letters 26 7649305
2010 Corepressors TLE1 and TLE3 interact with HESX1 and PROP1. Molecular endocrinology (Baltimore, Md.) 25 20181723
1989 Localization of atrial natriuretic factor (ANF) binding sites in the central nervous system of the frog. The Journal of comparative neurology 25 2522951
1988 ANF and exocrine pancreas: ultrastructural autoradiographic localization in acinar cells. The American journal of physiology 25 2964789
2005 Comparative analysis of the natriuretic peptide precursor gene cluster in vertebrates reveals loss of ANF and retention of CNP-3 in chicken. Developmental dynamics : an official publication of the American Association of Anatomists 24 15895405
1995 Effects of urodilatin in the rat kidney: comparison with ANF and interaction with vasoactive substances. Kidney international 24 7643524
1988 ANF inhibits vasopressin-induced Ca2+ mobilization and contraction in glomerular mesangial cells. The American journal of physiology 24 2972215
2012 Characterization of a long-acting recombinant human serum albumin-atrial natriuretic factor (ANF) expressed in Pichia pastoris. Regulatory peptides 23 22296859
2008 A novel SNP of the Hesx1 gene in bovine and its associations with average daily gain. Molecular biology reports 23 18853282
2005 Osteoblast calcium-sensing receptor has characteristics of ANF/7TM receptors. Journal of cellular biochemistry 23 15962313
1992 Basal and volume expansion-stimulated plasma atrial natriuretic peptide concentrations and hemodynamics in conscious rats: effects of SCH 39.370, an endopeptidase inhibitor, and C-ANF-(4-23), a clearance receptor ligand. Endocrinology 23 1531129
2014 Molecular analysis of PROP1, POU1F1, LHX3, and HESX1 in Turkish patients with combined pituitary hormone deficiency: a multicenter study. Endocrine 22 25500790
2013 Identification of HESX1 mutations in Kallmann syndrome. Fertility and sterility 22 23465708
2011 Ca2+-induced PARP-1 activation and ANF expression are coupled events in cardiomyocytes. The Biochemical journal 22 21635224
1995 Catalytic activation of guanylate cyclase/atrial natriuretic factor receptor by combined effects of ANF and GTP gamma S in plasma membranes of Leydig tumor cells: involvement of G-proteins. Archives of biochemistry and biophysics 22 7840642
1990 Dehydration increases the density of C receptors for ANF on rat glomerular membranes. The American journal of physiology 22 2158751
2016 HESX1 mutations in patients with congenital hypopituitarism: variable phenotypes with the same genotype. Clinical endocrinology 21 27000987
2006 Conserved regulatory elements establish the dynamic expression of Rpx/HesxI in early vertebrate development. Developmental biology 21 16527264
1999 HESX1: a novel gene implicated in a familial form of septo-optic dysplasia. Acta paediatrica (Oslo, Norway : 1992). Supplement 21 10626545
1995 ANF and angiotensin II interact via kinases in the proximal straight tubule. The American journal of physiology 21 7537466
1991 Studies of ANF processing and secretion using a primary cardiocyte culture model. Canadian journal of physiology and pharmacology 21 1838022
2007 DNMT1 interacts with the developmental transcriptional repressor HESX1. Biochimica et biophysica acta 20 17931718
2000 Sulfonylurea receptor ligands modulate stretch-induced ANF secretion in rat atrial myocyte culture. American journal of physiology. Heart and circulatory physiology 20 10843902
1993 Ascorbic acid enhances forskolin-induced cyclic AMP production and pro-ANF mRNA expression of hypothalamic neurons in culture. Endocrinology 20 8386616
1992 ANF and bradykinin synergistically inhibit transport in M-1 cortical collecting duct cell line. The American journal of physiology 20 1322053
1987 Comparative effect of ANF and various diuretics on isolated nephron segments. Kidney international 20 2953924
1991 CGRP and ANF cause relaxation of opossum internal anal sphincter via different mechanisms. The American journal of physiology 19 1852117
1990 Photoaffinity labelling of atrial natriuretic factor (ANF)-R1 receptor by underivatized 125I-ANF. Involvement of lipid peroxidation. The Biochemical journal 18 2159278
2010 Candidate gene sequencing of LHX2, HESX1, and SOX2 in a large schizencephaly cohort. American journal of medical genetics. Part A 17 20949537
1994 Functional characterization of ribozymes expressed using U1 and T7 vectors for the intracellular cleavage of ANF mRNA. Biochemistry 16 7918434
1992 The pharmacokinetics of 125I-atrial natriuretic factor in anaesthetized rats. Effects of neutral endopeptidase inhibition with candoxatrilat and of ANF-C receptor blockade. Biochemical pharmacology 16 1417928
1991 Developing essential hypertension: a syndrome involving ANF deficiency? Canadian journal of physiology and pharmacology 16 1838026
1991 Neutral metalloendopeptidase inhibitors as ANF potentiators: sites and mechanisms of action. Canadian journal of physiology and pharmacology 16 1838029
1991 Proteinase activities in bovine atrium and the possible role of mast cell tryptase in the processing of atrial natriuretic factor (ANF). Comparative biochemistry and physiology. B, Comparative biochemistry 16 1838723

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