Affinage

CRX

Cone-rod homeobox protein · UniProt O43186

Length
299 aa
Mass
32.3 kDa
Annotated
2026-06-09
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CRX is a paired-like OTX-family homeodomain transcription factor that drives terminal differentiation of retinal photoreceptors and regulates pineal gene expression by binding TAAT-core consensus elements upstream of photoreceptor- and pineal-specific genes and transactivating them (PMID:9390562, PMID:9390516, PMID:9465110). Genome-wide it occupies thousands of cis-regulatory regions around photoreceptor genes, controlling downstream photoreceptor transcription factors and physiology genes through clustered binding sites with spacing- and orientation-dependent synergy (PMID:20693478). Its homeodomain mediates DNA binding while the C-terminal OTX tail/WSP effector domain mediates transcriptional activation; an NLS within residues 88–98 directs nuclear import (PMID:10984472, PMID:11971869, PMID:10967037). CRX activates transcription by recruiting HAT co-activators (STAGA, CBP, p300, GCN5), whose binding precedes histone H3 acetylation and chromatin opening at a subset of CRX-dependent sites during photoreceptor differentiation (PMID:17656371, PMID:30068366, PMID:18927113). It acts combinatorially with partners including NRL, Nr2e3, Sp4, and Rax to activate rod genes such as rhodopsin and PDE6A while NRL/Nr2e3 cooperation can repress cone opsins in rods (PMID:9390516, PMID:10887186, PMID:15689355, PMID:15781457, PMID:25986607, PMID:15001570). CRX also lies upstream of OTX2-dependent NRL expression to consolidate rod fate, and is regulated by inhibitory cofactors (phosducin/PhLOP1, PANKY/Ankrd33, Samd7) (PMID:24382353, PMID:10866677, PMID:20026326, PMID:23565263). Loss of CRX blocks outer-segment morphogenesis, disorganizes presynaptic active-zone/ribbon synapse assembly, and drastically reduces photoreceptor gene expression (PMID:10581037, PMID:15676071, PMID:30084954). Dominant and recessive CRX mutations cause cone-rod dystrophy and Leber congenital amaurosis through mechanistically distinct routes—hypomorphic loss of DNA binding (R90W), antimorphic interference (E168d2), or gain-of-function effects via enhanced transactivation (E80A) or altered binding specificity (K88N) (PMID:9390563, PMID:9931337, PMID:24516401, PMID:37963072).

Mechanistic history

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

    Established CRX as a photoreceptor-specific homeodomain transcription factor that binds TAAT-core elements upstream of photoreceptor genes and is required for terminal photoreceptor formation, answering what controls photoreceptor gene activation.

    Evidence In vitro DNA binding, transactivation reporters, retroviral overexpression and dominant-negative vectors in mouse retina; yeast one-hybrid against the rhodopsin promoter showing synergy with NRL

    PMID:9390516 PMID:9390562

    Open questions at the time
    • Direct co-activator recruitment not yet identified
    • Genome-wide target set unknown
  2. 1998 Medium

    Extended CRX function beyond the retina by showing it binds the pineal regulatory element and activates pineal-specific gene promoters, linking CRX to pineal/circadian gene expression.

    Evidence EMSA and transactivation reporter assays on PINA, NAT, HIOMT promoters

    PMID:9465110

    Open questions at the time
    • No in vivo pineal loss-of-function at this stage
    • Cofactor requirements in pineal unknown
  3. 1997 High

    Connected CRX directly to inherited retinal disease, showing CRX is essential for photoreceptor maintenance and that mutations act via haploinsufficiency or dominant-negative effects.

    Evidence Mutational analysis of human cone-rod dystrophy families with functional mapping to homeodomain and WSP motif

    PMID:9390563

    Open questions at the time
    • Molecular distinction between haploinsufficiency and dominant-negative not yet resolved
  4. 1999 High

    Defined the in vivo requirement for CRX by showing knockout mice fail outer-segment formation, lack ERG responses, and lose photoreceptor and pineal gene expression, establishing CRX as essential for terminal differentiation.

    Evidence Targeted gene disruption in mouse, ERG, gene expression analysis; EMSA/transactivation of R90W LCA mutant

    PMID:10581037 PMID:9931337

    Open questions at the time
    • Mechanism of outer-segment failure unresolved
    • Whether defect is developmental or maintenance unclear
  5. 2000 High

    Mapped CRX functional architecture and partner interfaces, defining the homeodomain for DNA binding, the OTX tail/WSP for activation, the NLS at 88–98, and the NRL leucine-zipper interface for synergy.

    Evidence Deletion analysis, EMSA, GST pull-down, yeast two-hybrid, GFP localization in HEK293T

    PMID:10887186 PMID:10967037 PMID:10984472

    Open questions at the time
    • Co-activator identity still unknown
    • Structural basis of NRL synergy not solved
  6. 2001 High

    Identified inhibitory regulators of CRX, showing phosducin/PhLOP1 and polyglutamine-expanded ataxin-7 bind CRX and suppress its transactivation, linking CRX dysfunction to SCA7 retinal degeneration.

    Evidence Yeast two-hybrid, GST pull-down, Co-IP, EMSA, IHC, SCA7 transgenic mice

    PMID:10866677 PMID:11580893

    Open questions at the time
    • Physiological role of phosducin-CRX interaction in vivo unclear
  7. 2003 High

    Resolved the ataxin-7/CRX repression mechanism, mapping interaction to the CRX glutamine-rich region and the polyQ tract and showing both co-occupy the rhodopsin enhancer, explaining transcriptional dysregulation in SCA7.

    Evidence Co-IP truncation mapping, transactivation assays, ChIP

    PMID:14613968

    Open questions at the time
    • How polyQ expansion converts ataxin-7 to a repressor not defined
  8. 2005 High

    Expanded the combinatorial CRX regulatory network by showing Nr2e3 and Sp4 physically interact with CRX and co-occupy photoreceptor promoters to modulate rod versus cone gene programs.

    Evidence Yeast two-hybrid, Co-IP with domain mapping, ChIP, reporter assays, IHC

    PMID:15689355 PMID:15781457

    Open questions at the time
    • Quantitative contribution of each partner to gene selection unclear
  9. 2007 High

    Established the chromatin-level mechanism of CRX activation, showing it recruits HAT co-activators (STAGA, CBP, p300) and that CRX binding precedes H3 acetylation and NRL/Nr2e3/Pol II recruitment during development.

    Evidence Protein interaction assays, qRT-PCR, ChIP in developing retina, Crx-/- analysis; later RS1 promoter ChIP for CBP/p300/GCN5

    PMID:17656371 PMID:18927113

    Open questions at the time
    • Order of co-activator assembly across all loci not generalized
  10. 2010 High

    Defined the genome-wide CRX cis-regulatory landscape, revealing thousands of bound regions, regulation of downstream transcription factors, and rod- versus cone-specific binding distinguished using Nrl-/- retinas.

    Evidence CRX ChIP-seq in wild-type and Nrl-/- mouse retinas

    PMID:20693478

    Open questions at the time
    • Which bound sites are functionally required not determined from binding alone
  11. 2014 High

    Placed CRX upstream of OTX2/NRL for rod fate consolidation and defined distinct disease-allele mechanisms, separating antimorphic (E168d2) from hypomorphic (R90W) effects.

    Evidence CrxRip mutant mouse, RNA-seq, OTX2 ChIP at Nrl promoter, AAV rescue; E168d2 and R90W knock-in mice with ERG, histology, qRT-PCR, transactivation

    PMID:24382353 PMID:24516401

    Open questions at the time
    • Dose-dependent dominant interference mechanism at molecular level incomplete
  12. 2018 High

    Distinguished which CRX binding events drive chromatin remodeling versus passive occupancy, and extended CRX function to presynaptic active-zone and ribbon synapse organization.

    Evidence ATAC-seq in WT and Crx-/- developing retina integrated with ChIP-seq/transcriptome; IHC of Crx mutant retinas with ChIP-seq/transcriptome integration

    PMID:30068366 PMID:30084954

    Open questions at the time
    • Features predicting CRX-dependent vs independent sites only partially defined
    • CRX does not control ribbon formation itself
  13. 2023 High

    Demonstrated gain-of-function disease mechanisms, showing E80A enhances transactivation while K88N redirects DNA-binding specificity to ectopic sites, distinct from loss-of-function alleles.

    Evidence E80A and K88N knock-in mice with in vitro/in vivo functional analysis and genome-wide DNA-binding profiling

    PMID:37963072

    Open questions at the time
    • Downstream consequences of ectopic K88N binding on cell fate not fully traced
  14. 2024 High

    Resolved how CRX effector and DNA-binding domains shape the regulatory genome and the substitution constraints governing activity, including silencer derepression by effector-domain mutants and acidic-exposure-model behavior of the disordered effector domain.

    Evidence MPRA in knock-in retina explants with chromatin accessibility analysis; deep mutational scan of ~2000 variants in cell-based reporter

    PMID:38355306 PMID:39322280

    Open questions at the time
    • Mechanism of enhancer/silencer pleiotropy not structurally explained

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CRX integrates its many cofactors and chromatin co-activators to achieve locus-specific enhancer versus silencer outcomes, and the structural basis of combinatorial partner selection, remains open.
  • No structure of CRX complexes with partners
  • Rules governing pleiotropic element switching unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 7 GO:0140110 transcription regulator activity 6
Localization
GO:0005654 nucleoplasm 3 GO:0005634 nucleus 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1266738 Developmental Biology 3 R-HSA-4839726 Chromatin organization 3
Partners
ANKRD33ATAXIN-7NR2E3NRLOTX2PDCRAXSP4

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 CRX is a photoreceptor-specific otx-like homeodomain transcription factor that binds the sequence TAATCC/A found upstream of photoreceptor-specific genes (including opsin genes) and transactivates them; overexpression increased rod photoreceptor clones and a dominant-negative form blocked outer segment and terminal formation. In vitro DNA binding, transactivation reporter assays, retroviral overexpression and dominant-negative retroviral vector in mouse retina Cell High 9390516 9390562
1997 CRX binds the Ret4, Ret1, and BAT-1 sites in the rhodopsin promoter and transactivates the rhodopsin promoter reporter; it also binds and transactivates promoters of IRBP, beta-phosphodiesterase, and arrestin genes. Its transcriptional activity is synergistic with NRL. Yeast one-hybrid screen, in vitro binding (recombinant protein), transient transfection transactivation assay Neuron High 9390516
1997 Mutations in CRX (E80A missense; E168Δ1bp frameshift) cause autosomal dominant cone-rod dystrophy, demonstrating CRX is essential for photoreceptor maintenance; mechanisms include haploinsufficiency or dominant negative effect. Mutational analysis of human families, functional mapping of mutations within conserved homeodomain and WSP motif Cell High 9390563
1999 Crx knockout mice fail to form photoreceptor outer segments, lack rod and cone ERG responses, and show reduced expression of photoreceptor- and pineal-specific genes; circadian entrainment is also attenuated, placing CRX as essential for photoreceptor terminal differentiation and pineal gene expression. Targeted gene disruption (knockout mouse), ERG, gene expression analysis Nature genetics High 10581037
2000 The leucine zipper of NRL physically interacts with the CRX homeodomain (and flanking glutamine-rich/basic regions) to mediate transcriptional synergy on the rhodopsin promoter; disease-causing CRX homeodomain mutations R41W and R90W reduce both DNA binding and NRL interaction. Yeast two-hybrid, GST pull-down assay, deletion analysis, transactivation reporter assay The Journal of biological chemistry High 10887186
1999 The CRX R90W homeodomain mutation causes recessive LCA; mutant CRX(R90W) shows decreased binding to rhodopsin promoter cis-elements and significantly reduced transactivation and NRL synergy, demonstrating that DNA binding and transactivation capacity are required for photoreceptor gene expression. In vitro EMSA (DNA binding), transient transfection transactivation assay, patient mutation identification Human molecular genetics High 9931337
2000 The nuclear localization signal (NLS) of CRX resides between residues 88–98 in the C-terminal portion of the homeodomain; the R90W LCA mutation disrupts nuclear transport, resulting in cytoplasmic mislocalization. GFP fusion protein constructs with C-terminal deletions and point mutations expressed in HEK293T cells, fluorescence/confocal microscopy Investigative ophthalmology & visual science Medium 10967037
2000 CRX functional domains: the homeodomain is required for DNA binding; the OTX tail and WSP domain are important for transcriptional activation; synergy with NRL is maintained regardless of which CRX activation domain variant is used. Deletion analysis combined with EMSA (DNA binding) and transient transfection transactivation assays The Journal of biological chemistry Medium 10984472
2000 Phosducin (Phd) and PhLOP1 physically interact with CRX (interaction domain maps to the carboxyl terminus of Phd isoforms) and inhibit CRX transactivation by ~50–70% without affecting CRX DNA binding; Phd co-localizes with CRX in cone inner segments. Yeast two-hybrid, in vitro binding assay, GST pull-down, transient cotransfection reporter assay, EMSA, immunohistochemistry Molecular and cellular biology High 10866677
2001 Polyglutamine-expanded ataxin-7 interacts with CRX (yeast two-hybrid and co-immunoprecipitation), co-localizes with CRX in photoreceptors, and suppresses CRX transactivation; in SCA7 transgenic mice, CRX DNA-binding activity is reduced and CRX-regulated photoreceptor genes are down-regulated. Yeast two-hybrid, co-immunoprecipitation, EMSA, RT-PCR, transgenic mouse model Neuron High 11580893
2002 CRX mutations affecting the C-terminal region (amino acids 200–284) markedly reduce transcriptional activation; homeodomain missense mutations decrease or alter DNA binding (by EMSA); truncated CRX proteins lacking the C-terminus are transcriptionally inactive, supporting the role of the activation domain in photoreceptor gene regulation. Transient transfection transactivation assays, EMSA with homeodomain peptides, deletion analysis Human molecular genetics High 11971869
2003 CRX's interaction with ataxin-7 maps to CRX's glutamine-rich region (not its homeodomain) and ataxin-7's Crx-binding domain maps to its polyglutamine tract; ataxin-7 must localize to the nucleus to repress CRX transactivation; CRX and ataxin-7 co-occupy rhodopsin promoter/enhancer regions in vivo. Co-immunoprecipitation with truncation and point mutants, CRX transactivation assay in HEK293, chromatin immunoprecipitation (ChIP) Human molecular genetics High 14613968
2005 Nr2e3 (nuclear receptor) physically interacts with CRX through their respective DNA-binding domains; Nr2e3 is recruited to photoreceptor gene promoters/enhancers in a CRX-dependent manner; together, Nr2e3 and CRX enhance rhodopsin transcription but repress S- and M-cone opsin transcription in rods. Yeast two-hybrid, co-immunoprecipitation, chromatin immunoprecipitation (ChIP), transient transfection reporter assay, immunohistochemistry Human molecular genetics High 15689355
2005 Sp4 interacts physically with CRX (co-immunoprecipitation; zinc finger domains of Sp proteins and CRX homeodomain are required) and synergizes with CRX to activate rod opsin promoter; Sp4 and CRX co-occupy the rod opsin promoter in retinal chromatin. Co-immunoprecipitation, transient transfection reporter assay, ChIP, in situ hybridization/immunohistochemistry The Journal of biological chemistry High 15781457
2007 CRX activates opsin transcription by recruiting HAT-containing co-activators (STAGA, CBP, p300) to photoreceptor gene promoter/enhancer regions; in developing retina, CRX binding precedes HAT recruitment, histone H3 acetylation, and subsequent binding of NRL/Nr2e3 and RNA Pol II; in Crx-/- retinas, HAT association and H3 acetylation at opsin loci are significantly reduced. Protein-protein interaction assays, quantitative RT-PCR, chromatin immunoprecipitation (ChIP) in developing mouse retina, analysis of Crx-/- mice Human molecular genetics High 17656371
2010 ChIP-seq of CRX in adult mouse retina identified thousands of CRX-bound cis-regulatory regions around photoreceptor genes; CRX directly regulates downstream photoreceptor transcription factors and their target genes via spatially distributed regulatory elements; CRX-bound regions act synergistically and contain multiple binding sites with spacing- and orientation-dependent effects; comparison with Nrl-/- retinas identified rod- and cone-specific CRX-bound regions. ChIP-seq (CRX), comparison in wild-type and Nrl-/- retinas Genome research High 20693478
1998 CRX binds a pineal regulatory element (PIRE; consensus TAATC/T) present in multiple copies in the PINA, NAT, and HIOMT promoters and transactivates PIRE-reporter constructs, indicating CRX regulates pineal-specific gene expression. In vitro binding (EMSA), transactivation reporter assay Proceedings of the National Academy of Sciences of the United States of America Medium 9465110
2004 Both CRX and NRL are required for full transcriptional activity of the PDE6A gene; CRX alone modestly transactivates the PDE6A promoter; co-expression of CRX and NRL produces >100-fold increase; DNase I footprinting identified three CRX binding sites (all requiring TAAT core) in the PDE6A proximal promoter; Pde6a mRNA is reduced 87% in Crx-/- mice. Transient transfection reporter assay, DNase I footprinting, EMSA, mutation analysis, RT-PCR in Crx-/- and Nrl-/- mice The Journal of biological chemistry High 15001570
2005 Ultrastructural analysis of Crx-/- mouse retina showed outer segment morphogenesis is blocked at the elongation stage (failure to form phototransduction apparatus) and photoreceptors exhibit severely abnormal synaptic endings in the outer plexiform layer, revealing a role for CRX in photoreceptor synaptogenesis. Electron microscopy of Crx-/- mouse retina BMC neuroscience Medium 15676071
2014 Dominant CRX frameshift mutations (CrxRip) cause congenital blindness by abolishing OTX2 binding at the Nrl promoter, leading to progressive loss of NRL in developing rods; ectopic OTX2 expression rescues rod differentiation defect in CrxRip/+ mice, placing CRX upstream of OTX2-dependent NRL expression for rod fate consolidation. Spontaneous mutant mouse characterization, RNA-seq, ChIP (OTX2 at Nrl promoter), AAV-mediated rescue expression in mouse retina The Journal of clinical investigation High 24382353
2014 Knock-in mouse models (E168d2 and R90W) demonstrate mechanistically distinct CRX disease classes: E168d2 CRX protein fails to activate transcription and interferes more strongly with WT CRX (antimorphic), while R90W has reduced DNA binding and weaker dominant effects; E168d2/+ retinas show higher mutant CRX levels than WT, and reducing mutant allele expression (E168d2neo/+) markedly ameliorates phenotype. Knock-in mouse models, ERG, histology, qRT-PCR for target genes, in vitro transactivation assay PLoS genetics High 24516401
2015 Rax homeoprotein co-immunoprecipitates with CRX in cultured cells, co-localizes with CRX in maturing photoreceptors, and cooperatively transactivates rhodopsin and cone opsin promoters with CRX in luciferase assays; conditional Rax knockout reduces rod/cone photoreceptor gene expression. Co-immunoprecipitation, luciferase transactivation assay, conditional knockout mouse, immunohistochemistry Molecular and cellular biology Medium 25986607
2018 CRX controls the establishment of the cytomatrix active zone (CAZ) and anchoring of ribbon synapses in photoreceptor presynaptic terminals; integrated CRX/NRL ChIP-seq with transcriptome of Crx mutants identified CRX target genes encoding CAZ and synaptic vesicle proteins (REEP6, PSD95, MPP4, UNC119, UNC13, RGS7, RGS11); CRX does not control ribbon formation itself. Immunohistochemistry of Crx-/-, CrxRip/+ and CrxRip/Rip mouse retinas, transcriptome analysis, CRX/NRL ChIP-seq data integration Human molecular genetics High 30084954
2018 CRX is required for chromatin remodeling at only a subset (~subset) of its >6000 binding sites; 'CRX Dependent' sites undergo retina/neuron-specific chromatin opening during photoreceptor differentiation and are distinguished by unique nucleotide/motif content; genes near these sites encode photoreceptor physiology proteins and show significantly reduced transcription in Crx-deficient retinas. ATAC-seq/chromatin profiling in developing wild-type and Crx-/- retinas, cross-referencing with ChIP-seq and transcriptome data Epigenetics & chromatin High 30068366
2009 PANKY (Ankrd33), a photoreceptor-specific ankyrin repeat protein directly regulated by CRX, physically inhibits CRX DNA-binding activity (EMSA) and acts as a transcriptional cofactor suppressing CRX-activated photoreceptor genes. EMSA, transactivation assay, immunohistochemistry, retinal expression analysis FEBS letters Medium 20026326
2008 CRX controls retinal expression of the RS1 (retinoschisis) gene through two conserved CRX-responsive elements (CRE) in the proximal RS1 promoter; ChIP associates the RS1 promoter in vivo with CRX, CBP, p300, GCN5, and acetylated histone H3; mutation of either CRE strongly decreases RS1 expression in transgenic Xenopus. Reporter assays (site-directed mutagenesis), ChIP, transgenic Xenopus laevis Nucleic acids research High 18927113
2013 Samd7 is a CRX-regulated transcriptional repressor: its first intron enhancer contains evolutionarily conserved CRX binding motifs; CRX shRNA knockdown reduces Samd7 reporter activity and endogenous protein; Samd7 in turn suppresses CRX-dependent transcription in dose-dependent manner in reporter assays. ChIP-seq data analysis, in vitro electroporation reporter assay in mouse retina, shRNA knockdown, luciferase reporter assay PloS one Medium 23565263
2014 In the rat pineal gland, CRX transcript and protein levels exhibit a circadian rhythm peaking at night under sympathetic nervous system control; shRNA knockdown of Crx in primary rat pinealocytes reduces Aanat expression, while Crx overexpression induces Aanat transcription, demonstrating CRX directly promotes nocturnal AANAT expression to facilitate melatonin synthesis. Adenovirus-mediated shRNA knockdown and overexpression in primary pinealocytes, qRT-PCR, circadian expression analysis Endocrinology Medium 24877634
2019 Frmpd1 is transcribed from a retina-specific alternative promoter containing NRL and CRX binding sites; CRX and NRL bind the proximal Frmpd1 promoter (-8 to +33 bp) and are necessary for reporter activation in vitro and in vivo; CRISPR/Cas9 deletion of this NRL/CRX binding region completely eliminates Frmpd1 expression in rods. Electroporation reporter assay in mouse retina in vivo, EMSA, CRISPR/Cas9 genomic deletion Human molecular genetics High 30445545
2023 CRX homeodomain mutations E80A and K88N cause dominant retinopathies through distinct gain-of-function mechanisms: E80A increases CRX-mediated transactivation of canonical target genes in developing photoreceptors; K88N alters CRX DNA-binding specificity, causing binding at ectopic genomic sites and severe perturbation of CRX target gene expression. Knock-in mouse models (E80A, K88N), integrated molecular and functional analysis in vitro and in vivo, genome-wide DNA-binding profiling eLife High 37963072
2024 Pathogenic CRX variants in the DNA-binding domain (R90W) and transcriptional effector domain (E168d2) affect overlapping sets of enhancers; E168d2 has distinct additional effects on silencers, including derepression of silencers near cone photoreceptor genes; some regulatory elements are pleiotropic (switching between silencer and enhancer activity depending on CRX effector domain status). Massively parallel reporter assays (MPRA) in mouse retina explants carrying knock-in variants, chromatin accessibility analysis Genome research High 38355306
2024 Deep mutational scanning of nearly all single amino acid substitutions in CRX revealed that the structured homeodomain follows position-specific constraints on substitution for transcriptional activity, while the intrinsically disordered transcriptional effector domain follows compositional constraints consistent with the acidic exposure model of transcriptional activation. Deep mutational scan (cell-based transcriptional reporter assay), ~2000 variants assessed Genome research High 39322280
2009 NR2E3 DNA-binding domain mutations impair in vivo NR2E3/CRX complex formation (measured by BRET2); the adRP-linked G56R mutant retains CRX interaction but enhances cone opsin repression, while other DBD mutants lose CRX interaction, supporting mechanistically distinct disease pathways. Bioluminescence Resonance Energy Transfer (BRET2) in transfected HEK293T cells, transactivation/transrepression reporter assays PloS one Medium 19823680

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Crx, a novel otx-like homeobox gene, shows photoreceptor-specific expression and regulates photoreceptor differentiation. Cell 759 9390562
1997 Crx, a novel Otx-like paired-homeodomain protein, binds to and transactivates photoreceptor cell-specific genes. Neuron 613 9390516
1997 Cone-rod dystrophy due to mutations in a novel photoreceptor-specific homeobox gene (CRX) essential for maintenance of the photoreceptor. Cell 486 9390563
1999 Retinopathy and attenuated circadian entrainment in Crx-deficient mice. Nature genetics 452 10581037
2009 Transplantation of human embryonic stem cell-derived photoreceptors restores some visual function in Crx-deficient mice. Cell stem cell 445 19128794
1998 A range of clinical phenotypes associated with mutations in CRX, a photoreceptor transcription-factor gene. American journal of human genetics 229 9792858
2005 The photoreceptor-specific nuclear receptor Nr2e3 interacts with Crx and exerts opposing effects on the transcription of rod versus cone genes. Human molecular genetics 228 15689355
2001 Polyglutamine-expanded ataxin-7 antagonizes CRX function and induces cone-rod dystrophy in a mouse model of SCA7. Neuron 194 11580893
2000 The leucine zipper of NRL interacts with the CRX homeodomain. A possible mechanism of transcriptional synergy in rhodopsin regulation. The Journal of biological chemistry 191 10887186
2010 CRX ChIP-seq reveals the cis-regulatory architecture of mouse photoreceptors. Genome research 173 20693478
1999 Leber congenital amaurosis caused by a homozygous mutation (R90W) in the homeodomain of the retinal transcription factor CRX: direct evidence for the involvement of CRX in the development of photoreceptor function. Human molecular genetics 162 9931337
2003 Otd/Crx, a dual regulator for the specification of ommatidia subtypes in the Drosophila retina. Developmental cell 113 12967559
1998 Retinal degenerations with truncation mutations in the cone-rod homeobox (CRX) gene. Investigative ophthalmology & visual science 113 9804150
2013 The TLR4 antagonist CRX-526 protects against advanced diabetic nephropathy. Kidney international 112 23423259
2004 Zebrafish cone-rod (crx) homeobox gene promotes retinogenesis. Developmental biology 109 15081370
1998 A pineal regulatory element (PIRE) mediates transactivation by the pineal/retina-specific transcription factor CRX. Proceedings of the National Academy of Sciences of the United States of America 100 9465110
2001 Temporal and spatial expression patterns of the CRX transcription factor and its downstream targets. Critical differences during human and mouse eye development. Human molecular genetics 84 11468275
2021 Gene Therapy of Dominant CRX-Leber Congenital Amaurosis using Patient Stem Cell-Derived Retinal Organoids. Stem cell reports 81 33513359
2013 Developing rods transplanted into the degenerating retina of Crx-knockout mice exhibit neural activity similar to native photoreceptors. Stem cells (Dayton, Ohio) 76 23495178
2002 The mouse Crx 5'-upstream transgene sequence directs cell-specific and developmentally regulated expression in retinal photoreceptor cells. The Journal of neuroscience : the official journal of the Society for Neuroscience 75 11880494
2001 Dominant Leber congenital amaurosis, cone-rod degeneration, and retinitis pigmentosa caused by mutant versions of the transcription factor CRX. Human mutation 72 11748842
2002 Functional analysis of cone-rod homeobox (CRX) mutations associated with retinal dystrophy. Human molecular genetics 71 11971869
2007 Crx activates opsin transcription by recruiting HAT-containing co-activators and promoting histone acetylation. Human molecular genetics 70 17656371
2003 Interference of Crx-dependent transcription by ataxin-7 involves interaction between the glutamine regions and requires the ataxin-7 carboxy-terminal region for nuclear localization. Human molecular genetics 68 14613968
2014 OTX2 loss causes rod differentiation defect in CRX-associated congenital blindness. The Journal of clinical investigation 64 24382353
2009 Differential CRX and OTX2 expression in human retina and retinoblastoma. Journal of neurochemistry 64 19686387
2000 Modulation of CRX transactivation activity by phosducin isoforms. Molecular and cellular biology 63 10866677
2014 The phenotypic variability of retinal dystrophies associated with mutations in CRX, with report of a novel macular dystrophy phenotype. Investigative ophthalmology & visual science 62 25270190
2005 Synaptogenesis and outer segment formation are perturbed in the neural retina of Crx mutant mice. BMC neuroscience 62 15676071
2000 Functional domains of the cone-rod homeobox (CRX) transcription factor. The Journal of biological chemistry 61 10984472
2020 Functional and Evolutionary Diversification of Otx2 and Crx in Vertebrate Retinal Photoreceptor and Bipolar Cell Development. Cell reports 59 31968244
2014 Mechanistically distinct mouse models for CRX-associated retinopathy. PLoS genetics 56 24516401
2002 Distinct functions of photoreceptor cell-specific nuclear receptor, thyroid hormone receptor beta2 and CRX in one photoreceptor development. Investigative ophthalmology & visual science 54 12407160
2010 Two novel CRX mutant proteins causing autosomal dominant Leber congenital amaurosis interact differently with NRL. Human mutation 52 20513135
2014 Mechanisms of blindness: animal models provide insight into distinct CRX-associated retinopathies. Developmental dynamics : an official publication of the American Association of Anatomists 51 24888636
2015 Rax Homeoprotein Regulates Photoreceptor Cell Maturation and Survival in Association with Crx in the Postnatal Mouse Retina. Molecular and cellular biology 50 25986607
2007 Ontogenetic expression of the Otx2 and Crx homeobox genes in the retina of the rat. Experimental eye research 49 17467693
2004 Functional analysis of the rod photoreceptor cGMP phosphodiesterase alpha-subunit gene promoter: Nrl and Crx are required for full transcriptional activity. The Journal of biological chemistry 49 15001570
2000 A CRX null mutation is associated with both Leber congenital amaurosis and a normal ocular phenotype. Investigative ophthalmology & visual science 49 10892846
2015 PEG modified liposomes containing CRX-601 adjuvant in combination with methylglycol chitosan enhance the murine sublingual immune response to influenza vaccination. Journal of controlled release : official journal of the Controlled Release Society 48 26551346
2021 Allele-specific gene editing to rescue dominant CRX-associated LCA7 phenotypes in a retinal organoid model. Stem cell reports 47 34653402
2012 CRX variants in cone-rod dystrophy and mutation overview. Biochemical and biophysical research communications 44 22960069
2019 CRX Expression in Pluripotent Stem Cell-Derived Photoreceptors Marks a Transplantable Subpopulation of Early Cones. Stem cells (Dayton, Ohio) 43 30681766
2003 The mammalian Crx genes are highly divergent representatives of the Otx5 gene family, a gnathostome orthology class of orthodenticle-related homeogenes involved in the differentiation of retinal photoreceptors and circadian entrainment. Molecular biology and evolution 43 12654938
2018 CRX directs photoreceptor differentiation by accelerating chromatin remodeling at specific target sites. Epigenetics & chromatin 42 30068366
2009 CRX is a diagnostic marker of retinal and pineal lineage tumors. PloS one 42 19936203
2005 Sp4 is expressed in retinal neurons, activates transcription of photoreceptor-specific genes, and synergizes with Crx. The Journal of biological chemistry 40 15781457
2009 Mutations in the DNA-binding domain of NR2E3 affect in vivo dimerization and interaction with CRX. PloS one 38 19823680
2006 Docosahexaenoic acid promotes photoreceptor differentiation without altering Crx expression. Investigative ophthalmology & visual science 37 16799048
2012 Derivation of human differential photoreceptor-like cells from the iris by defined combinations of CRX, RX and NEUROD. PloS one 34 22558175
2005 Leukemia inhibitory factor blocks expression of Crx and Nrl transcription factors to inhibit photoreceptor differentiation. Investigative ophthalmology & visual science 33 15980254
2002 The rod cGMP-phosphodiesterase beta-subunit promoter is a specific target for Sp4 and is not activated by other Sp proteins or CRX. The Journal of biological chemistry 33 11943774
2008 Analysis of the Otd-dependent transcriptome supports the evolutionary conservation of CRX/OTX/OTD functions in flies and vertebrates. Developmental biology 32 18241855
2001 Autosomal dominant retinal degeneration and bone loss in patients with a 12-bp deletion in the CRX gene. Investigative ophthalmology & visual science 31 11328746
2001 Novel frameshift mutations in CRX associated with Leber congenital amaurosis. Human mutation 31 11748859
1997 A major cis activator of the IRBP gene contains CRX-binding and Ret-1/PCE-I elements. Molecular vision 30 9479006
2019 Pathogenicity discrimination and genetic test reference for CRX variants based on genotype-phenotype analysis. Experimental eye research 29 31626798
2006 Safety of the intranasal toll-like receptor 4 agonist CRX-675 in allergic rhinitis. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology 29 17069098
2015 Using Zinc Finger Nuclease Technology to Generate CRX-Reporter Human Embryonic Stem Cells as a Tool to Identify and Study the Emergence of Photoreceptors Precursors During Pluripotent Stem Cell Differentiation. Stem cells (Dayton, Ohio) 28 26608863
2014 Circadian dynamics of the cone-rod homeobox (CRX) transcription factor in the rat pineal gland and its role in regulation of arylalkylamine N-acetyltransferase (AANAT). Endocrinology 28 24877634
2008 Induction of functional photoreceptor phenotype by exogenous Crx expression in mouse retinal stem cells. Investigative ophthalmology & visual science 28 18172122
2002 Electrophysiologic and phenotypic features of an autosomal cone-rod dystrophy caused by a novel CRX mutation. Ophthalmology 27 12359607
2000 Nuclear trafficking of photoreceptor protein crx: the targeting sequence and pathologic implications. Investigative ophthalmology & visual science 27 10967037
2018 A complete, homozygous CRX deletion causing nullizygosity is a new genetic mechanism for Leber congenital amaurosis. Scientific reports 26 29568065
2014 Derivation of human differential photoreceptor cells from adult human dermal fibroblasts by defined combinations of CRX, RAX, OTX2 and NEUROD. Genes to cells : devoted to molecular & cellular mechanisms 26 24456169
2011 Crx broadly modulates the pineal transcriptome. Journal of neurochemistry 26 21797868
2015 OTX2 is a therapeutic target for retinoblastoma and may function as a common factor between C-MYC, CRX, and phosphorylated RB pathways. International journal of oncology 24 26397460
2008 Cone and cone-rod dystrophy segregating in the same pedigree due to the same novel CRX gene mutation. The British journal of ophthalmology 24 18653602
2007 Genotype-phenotype correlation in a German family with a novel complex CRX mutation extending the open reading frame. Ophthalmology 24 17320181
2004 Delayed expression of the Crx gene and photoreceptor development in the Chx10-deficient retina. Investigative ophthalmology & visual science 23 14744875
2001 Screening for CRX gene mutations in Chinese patients with Leber congenital amaurosis and mutational phenotype. Ophthalmic genetics 23 11449318
2018 Cone-rod homeobox CRX controls presynaptic active zone formation in photoreceptors of mammalian retina. Human molecular genetics 22 30084954
2016 CrxRdy Cat: A Large Animal Model for CRX-Associated Leber Congenital Amaurosis. Investigative ophthalmology & visual science 22 27427859
2023 Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms. eLife 21 37963072
2016 Autosomal recessive retinitis pigmentosa with homozygous rhodopsin mutation E150K and non-coding cis-regulatory variants in CRX-binding regions of SAMD7. Scientific reports 21 26887858
2017 A novel dominant CRX mutation causes adult-onset macular dystrophy. Ophthalmic genetics 20 28945142
2013 Sterile alpha motif containing 7 (samd7) is a novel crx-regulated transcriptional repressor in the retina. PloS one 20 23565263
2019 Homeobox genes in melatonin-producing pinealocytes: Otx2 and Crx act to promote hormone synthesis in the mature rat pineal gland. Journal of pineal research 19 30803008
2009 Robust marking of photoreceptor cells and pinealocytes with several reporters under control of the Crx gene. Developmental dynamics : an official publication of the American Association of Anatomists 19 19882727
2020 Association of CRX genotypes and retinal phenotypes confounded by variable expressivity and electronegative electroretinogram. Clinical & experimental ophthalmology 18 32112665
2002 Visual improvement in Leber congenital amaurosis and the CRX genotype. Ophthalmic genetics 18 11910559
2004 Novel 615delC mutation in the CRX gene in a Japanese family with cone-rod dystrophy. American journal of ophthalmology 17 15531334
2002 Novel de novo mutation in CRX gene in a Japanese patient with leber congenital amaurosis. American journal of ophthalmology 17 12208271
2024 Pathogenic variants in CRX have distinct cis-regulatory effects on enhancers and silencers in photoreceptors. Genome research 16 38355306
2009 Generation of light-sensitive photoreceptor phenotypes by genetic modification of human adult ocular stem cells with Crx. Investigative ophthalmology & visual science 16 19850845
2009 Panky, a novel photoreceptor-specific ankyrin repeat protein, is a transcriptional cofactor that suppresses CRX-regulated photoreceptor genes. FEBS letters 16 20026326
2019 Incomplete penetrance of CRX gene for autosomal dominant form of cone-rod dystrophy. Ophthalmic genetics 15 31215831
2012 Immunohistochemical expression of CRX in extracranial malignant small round cell tumors. The American journal of surgical pathology 15 22790857
2008 CRX controls retinal expression of the X-linked juvenile retinoschisis (RS1) gene. Nucleic acids research 15 18927113
2002 The effect of retinoids and butyrate on the expression of CRX and IRBP in retinoblastoma cells. Vision research 14 11934446
2019 Modeling of Photoreceptor Donor-Host Interaction Following Transplantation Reveals a Role for Crx, Müller Glia, and Rho/ROCK Signaling in Neurite Outgrowth. Stem cells (Dayton, Ohio) 13 30715780
2017 Nuclear CRX and FOXJ1 Expression Differentiates Non-Germ Cell Pineal Region Tumors and Supports the Ependymal Differentiation of Papillary Tumor of the Pineal Region. The American journal of surgical pathology 13 28719464
2013 Autosomal-dominant Leber Congenital Amaurosis Caused by a Heterozygous CRX Mutation in a Father and Son. Ophthalmic genetics 13 24093488
2010 A neuroanatomical and physiological study of the non-image forming visual system of the cone-rod homeobox gene (Crx) knock out mouse. Brain research 13 20438719
2002 Cloning and characterization of the canine photoreceptor specific cone-rod homeobox (CRX) gene and evaluation as a candidate for early onset photoreceptor diseases in the dog. Molecular vision 13 11951083
2000 Visual phenotype in patients with Arg41Gln and ala196+1bp mutations in the CRX gene. Ophthalmic genetics 13 10916183
2024 Mutational scanning of CRX classifies clinical variants and reveals biochemical properties of the transcriptional effector domain. Genome research 12 39322280
2019 Targeted deletion of an NRL- and CRX-regulated alternative promoter specifically silences FERM and PDZ domain containing 1 (Frmpd1) in rod photoreceptors. Human molecular genetics 12 30445545
2017 Crx-L253X Mutation Produces Dominant Photoreceptor Defects in TVRM65 Mice. Investigative ophthalmology & visual science 12 28903150
2003 Ocular findings in a Japanese family with an Arg41Trp mutation of the CRX gene. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 12 12819982

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