Affinage

RAX

Interferon-inducible double-stranded RNA-dependent protein kinase activator A · UniProt O75569

Length
313 aa
Mass
34.4 kDa
Annotated
2026-06-10
100 papers in source corpus 26 papers cited in narrative 26 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

The RAX symbol denotes two functionally distinct proteins that co-occur in this corpus. As a paired-type homeodomain transcription factor (RAX/Rx), it is a master regulator of vertebrate eye field specification, being essential for optic cup formation and, in gain-of-function, sufficient to induce ectopic retinal tissue and progenitor hyperproliferation (PMID:9177348). It acts cell-autonomously to build the neuroretina, retinal pigment epithelium, and distal optic stalk (PMID:19229337), and sits atop the retinal progenitor gene network: it is genetically epistatic to Pax6, with Otx2, Six3, and Pax6 upregulation in the optic vesicle requiring Rx (PMID:11105055), and is itself directly activated by Otx2 and Sox2 binding a conserved upstream element (PMID:18385377). Rx sustains progenitor proliferation in part through the Xhmgb3/c-myc axis (PMID:16445903) and directs cell fate by transactivating the Otx2 enhancer EELPOT, where it opposes NOTCH-HES signaling to govern photoreceptor determination (PMID:22090505). In maturing photoreceptors it physically interacts with Crx to transactivate rhodopsin and cone opsin promoters, and its postnatal loss specifically depletes cone cells (PMID:25986607, PMID:29665410). Human homeodomain mutations (Q147X, R192Q) cause autosomal recessive anophthalmia/microphthalmia (PMID:14662654). Beyond the eye, Rx serves as a selector gene for mediobasal hypothalamic (VMH/ARC) neuron identity (PMID:23283339), is required for early hypothalamic patterning via Shh (PMID:27212025), and drives tanycyte/ependymal differentiation and maintenance of the CSF-hypothalamus barrier (PMID:23939786). The same symbol independently encodes a dsRNA-binding PKR activator (RAX/PACT): under diverse stresses it is phosphorylated on serine 18, associates with and activates PKR to phosphorylate eIF2alpha, inhibit translation, and promote apoptosis (PMID:10336432, PMID:15299031, PMID:16861340). This stress-activator role also stimulates p53 sumoylation via Ubc9 to drive G1 arrest (PMID:22214662), and counterintuitively restrains PKR during anterior pituitary development (PMID:26414443).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1997 High

    Established that the Rx homeobox gene is necessary and sufficient for retinal tissue, defining it as a core eye-field determinant rather than a passive marker.

    Evidence Mouse null knockout (no optic cups) plus Xenopus RNA misexpression inducing ectopic retina; cDNA cloning revealing homeobox, octapeptide, and OAR domains

    PMID:9096350 PMID:9177348

    Open questions at the time
    • Direct transcriptional targets not yet identified
    • Domain contributions to activity not dissected
  2. 1999 High

    Identified a wholly separate RAX/PACT protein as a stress-activated, dsRNA-independent physiologic activator of PKR, linking cellular stress to translational shutdown.

    Evidence cDNA screen, in vitro PKR activation assay, RAX-PKR co-IP, and stress treatments (IL-3 withdrawal, arsenite, thapsigargin, H2O2)

    PMID:10336432

    Open questions at the time
    • Phosphorylation site responsible not yet mapped
    • Relationship (if any) to the retinal homeobox protein unaddressed
  3. 2000 High

    Placed Rx within the retinal progenitor regulatory hierarchy, showing it is epistatic to Pax6 and can bias progenitors toward Muller glia via Hes1/Notch1.

    Evidence Genetic epistasis in Rx-null and Pax6-null embryos; retroviral overexpression and Hes1/Notch1 reporter assays

    PMID:10839357 PMID:11105055

    Open questions at the time
    • Whether Rx binds these targets directly not shown
    • Mechanism of glial vs neuronal fate choice incomplete
  4. 2001 Medium

    Defined the downstream output of RAX/PACT-PKR signaling as eIF2alpha phosphorylation, translation arrest, and apoptosis, and showed ceramide as a physiological trigger.

    Evidence Ceramide treatment, RAX overexpression, 2-aminopurine PKR inhibition, eIF2alpha and viability assays; hypomorphic ey1 allele mapping (Met10Leu, leaky scanning)

    PMID:11148216 PMID:11668677

    Open questions at the time
    • Direct biochemical link from ceramide to RAX phosphorylation not resolved
    • ey1 finding pertains to homeobox gene translation, not PKR activator
  5. 2003 Medium

    Connected RAX homeodomain function to human disease, establishing the DNA-binding domain as functionally essential for eye development.

    Evidence Patient sequencing of compound heterozygote with Q147X and R192Q mutations plus in vitro biochemical characterization

    PMID:14662654

    Open questions at the time
    • Single family/study
    • Precise molecular defect of R192Q on target binding not fully resolved
  6. 2004 High

    Pinpointed serine 18 as the phospho-switch that converts RAX/PACT-PKR binding into PKR activation, separating association from activation.

    Evidence S18A non-phosphorylatable mutant as stable dominant negative; PKR kinase, eIF2alpha, and apoptosis assays after IL-3 withdrawal

    PMID:15299031

    Open questions at the time
    • Kinase phosphorylating S18 not identified
    • Structural basis of activation versus binding not resolved
  7. 2006 High

    Generalized RAX/PACT as the required activator of PKR across a broad stress repertoire and downstream inflammatory signaling, while in parallel work the retinal Rx network gained proliferation and regeneration outputs.

    Evidence siRNA knockdown and overexpression with PKR/eIF2alpha/IkB/IRF-1/STAT1 readouts and VSV infection; Xhmgb3-c-myc ChIP and morpholino in Xenopus

    PMID:16445903 PMID:16574643 PMID:16861340

    Open questions at the time
    • Specificity of stress-to-RAX coupling per stimulus unresolved
    • Xhmgb3 axis demonstrated only in Xenopus
  8. 2008 Medium

    Defined direct upstream activators of the retinal Rx gene and established cell-autonomy of Rx in ocular and pituitary tissue, while showing the PKR-activator RAX is essential for early embryogenesis.

    Evidence Otx2/Sox2 ChIP, reporter, and co-IP at CNS1; Rx-/- chimera fate tracing; Drosophila dRax mutants and mouse preimplantation lethality

    PMID:18385377 PMID:18634873 PMID:19229337

    Open questions at the time
    • Whether the early-lethal Rax is the PKR activator or homeobox gene needs disambiguation
    • Cell-autonomy mechanism (segregation timing) not molecularly explained
  9. 2011 High

    Identified the Otx2 enhancer EELPOT as a direct Rx target that opposes NOTCH-HES inputs to time photoreceptor fate, and showed Rx is required for retinal regeneration.

    Evidence EELPOT luciferase reporter, conditional Rax KO with in vivo Otx2 readout; Xenopus retinal resection with shRNA silencing and Rx rescue

    PMID:21334323 PMID:22090505

    Open questions at the time
    • Direct DNA-binding footprint within EELPOT not mapped
    • Regeneration mechanism beyond progenitor re-expression unclear
  10. 2012 Medium

    Extended the RAX/PACT stress program to p53 control, showing it promotes p53 sumoylation through Ubc9 to enforce G1 arrest.

    Evidence Co-IP of RAX-Ubc9 and p53-Ubc9, cell cycle flow cytometry, p53(K386R) and SENP1 and dominant-negative PKR controls

    PMID:22214662

    Open questions at the time
    • Single lab
    • Whether RAX directly bridges p53 and Ubc9 versus indirectly not resolved
  11. 2013 Medium

    Established Rx as a selector gene specifying mediobasal hypothalamic neuron identity, extending its master-regulator role beyond the eye.

    Evidence Conditional KO with Shh::Cre and Six3::Cre drivers, fate mapping, and cell-type marker IHC

    PMID:23283339

    Open questions at the time
    • Direct hypothalamic target genes not identified
    • Single lab
  12. 2014 Medium

    Connected the RAX/PACT-PKR cascade to ethanol neurotoxicity via an upstream miR-29b/SP1 regulatory layer controlling RAX abundance.

    Evidence miR-29b overexpression, ethanol treatment of cerebellar granule neurons, SP1/RAX/PKR expression and apoptosis assays; tanycyte/ependymal and barrier phenotyping in Rax haploinsufficient mice

    PMID:23939786 PMID:24554719

    Open questions at the time
    • Direct SP1 binding to RAX promoter not shown
    • Barrier-formation mechanism downstream of Rax in tanycytes unresolved
  13. 2015 High

    Defined the Rx-Crx cooperative module driving photoreceptor maturation and cone survival, and revealed a context-dependent negative regulation of PKR by RAX/PACT in pituitary development.

    Evidence Tamoxifen-inducible Rax iCKO with cone loss, opsin promoter reporters, Rax-Crx co-IP; rax-/- rescued by pkr-/-, PKR(K271R), and eIF2alpha(S51A) genetics

    PMID:25986607 PMID:26414443

    Open questions at the time
    • Why RAX activates PKR under stress but restrains it in pituitary unexplained
    • Whether pituitary RAX is homeobox or PKR-activator form needs clarity
  14. 2018 Medium

    Resolved that Rx is required in retinal progenitors both for proliferative maintenance and specifically for cone fate, refining its dual proliferation/differentiation role.

    Evidence Pax6alpha-Cre conditional KO with BrdU labeling and cell-type marker IHC across developmental stages

    PMID:29665410

    Open questions at the time
    • Mechanistic separation of proliferation from cone-specification functions incomplete
    • Direct cone-fate targets unknown
  15. 2021 Medium

    Established Rx+ tanycytes as a quiescent, injury-responsive stem-like population whose dysregulation by oncogenic Braf generates craniopharyngioma-like tumors.

    Evidence Rax-CreERT2 fate mapping, EdU cell-cycle analysis after injury, conditional Igf1r KO and Braf activation

    PMID:33863883

    Open questions at the time
    • Role of Rx transcriptional activity in tanycyte quiescence versus identity not dissected
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the single RAX symbol's two molecularly unrelated activities—a retinal/hypothalamic homeodomain transcription factor and a cytoplasmic dsRNA-binding PKR activator—are distinguished within the corpus, and what reconciles RAX/PACT acting as a PKR activator under stress yet a PKR restrainer in pituitary development.
  • No structural model unifying or separating the two activities
  • Tissue-specific isoform/gene assignment not clarified for each phenotype
  • Direct genome-wide targets of the homeodomain factor not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 3 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0140110 transcription regulator activity 3 GO:0003723 RNA binding 2
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-8953897 Cellular responses to stimuli 3
Partners
CRXOTX2P53PKRSOX2UBC9

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 The Rx homeobox gene is essential for vertebrate eye development: mouse embryos carrying a null allele fail to form optic cups and do not develop eyes, while misexpression in Xenopus induces ectopic retinal tissue and hyperproliferation in the neuroretina, establishing Rx as required for establishment and/or proliferation of retinal progenitor cells. Targeted gene knockout in mice (null allele); synthetic RNA injection in Xenopus embryos Nature High 9177348
1997 The Rax protein comprises a paired-type homeobox, an octapeptide motif, and a C-terminal OAR domain; it is expressed in the anterior neural fold and developing retina, consistent with a role in eye field specification and retinal progenitor proliferation/differentiation. cDNA cloning, amino acid sequence analysis, in situ hybridization Proceedings of the National Academy of Sciences of the United States of America Medium 9096350
2000 Rax (the retinal homeobox gene) promotes Müller glial cell formation from retinal progenitor cells; retroviral transduction of rax in retinal progenitors results in expression of glial markers, and cotransfection of rax with reporter constructs upregulates Hes1 and Notch1 transcription, placing rax upstream of a Hes1/Notch1 regulatory hierarchy that controls gliogenesis. Retroviral transduction in retinal progenitors; co-transfection reporter assays with Hes1 and Notch1 regulatory regions Neuron Medium 10839357
2000 Rx function is epistatic to Pax6 for retinal progenitor cell formation: in Rx-/- embryos, Otx2, Six3, and Pax6 fail to upregulate in the optic vesicle primordium, but in Pax6-null (Small eye) embryos, Rx shows normal expression in the optic vesicle, demonstrating that Pax6 expression in the retinal primordium requires Rx but Rx expression does not require Pax6. Genetic epistasis analysis using Rx-null and Pax6-null mouse embryos; in situ hybridization for downstream markers Genesis (New York, N.Y. : 2000) High 11105055
1999 RAX (the PKR-associated protein, mouse homolog of human PACT) directly activates PKR in vitro in the absence of dsRNA. Following stress stimuli (IL-3 deprivation, arsenite, thapsigargin, H2O2), RAX is rapidly phosphorylated, associates with PKR, and activates it, identifying RAX as a stress-activated physiologic activator of PKR that couples transmembrane stress signals to inhibition of protein synthesis. cDNA library screen; in vitro PKR activation assay; co-immunoprecipitation (RAX-PKR association); stress treatment of IL-3-dependent cells with phosphorylation analysis The Journal of biological chemistry High 10336432
2001 Ceramide activates PKR through RAX: ceramide treatment promotes RAX phosphorylation and eIF2α phosphorylation, inhibits protein synthesis, and potentiates apoptosis; overexpression of exogenous RAX enhances ceramide-induced killing, while the PKR inhibitor 2-aminopurine blocks both RAX-potentiated ceramide killing and ceramide-induced translation inhibition. Ceramide treatment of cells; overexpression of RAX; use of PKR inhibitor 2-aminopurine; eIF2α phosphorylation assay; cell viability assay The Journal of biological chemistry Medium 11148216
2001 The eyeless mouse mutation (ey1) results from a Met10→Leu substitution in an alternative AUG start codon of Rx/rax translated by leaky scanning, reducing Rx protein abundance. This hypomorphic allele is fully viable (unlike the null), establishing that the alternative translation initiation site is functionally important for normal Rx protein levels and eye development. Genome scan/linkage mapping; sequencing of Rx locus; comparison of hypomorphic vs. null phenotypes Genesis (New York, N.Y. : 2000) Medium 11668677
2003 Human RAX mutations (Q147X truncation and R192Q missense) within the DNA-binding homeodomain cause anophthalmia/microphthalmia in a compound heterozygote; in vitro biochemical characterization of these mutations established that the homeodomain is required for normal RAX function, consistent with autosomal recessive inheritance. Patient screening/sequencing; in vitro biochemical characterization of mutant proteins Human molecular genetics Medium 14662654
2004 RAX serine 18 phosphorylation is required for PKR activation: the non-phosphorylatable RAX(S18A) mutant can still bind dsRNA and associate with PKR but fails to activate PKR after stress, and its stable expression acts as a dominant negative, blocking eIF2α phosphorylation, delaying translation inhibition, and preventing apoptosis after IL-3 withdrawal. Site-directed mutagenesis (S18A); stable cell line expression; PKR kinase activity assay; eIF2α phosphorylation; cell death assay The Journal of biological chemistry High 15299031
2006 RAX (PKR activator) is required for PKR activation in response to a broad range of stresses including serum deprivation, IFNγ/TNFα, mitomycin C, and viral infection: 80% siRNA-mediated knockdown of RAX prevents PKR activation, eIF2α phosphorylation, IκB degradation, IRF-1 expression, and STAT1 phosphorylation, and enhances cell survival. Exogenous RAX (but not dominant-negative RAX(S18A)) sensitizes cells to these stresses. siRNA knockdown of RAX; exogenous RAX overexpression; PKR activity assay; immunoblot for eIF2α phosphorylation, IκB, IRF-1, STAT1; cell survival assay; viral infection assay (VSV) Blood High 16861340
2006 RAX interaction with PKR modulates ethanol-induced inhibition of protein synthesis and neuronal death: overexpression of wild-type RAX enhances ethanol-induced PKR/eIF2α phosphorylation and cell death, while dominant-negative RAX(S18A) blocks ethanol-promoted RAX-PKR association, eIF2α phosphorylation, translation inhibition, and cell death in cerebellar neurons. RAX overexpression and dominant-negative mutant expression in neuronal cells; PKR/eIF2α phosphorylation assay; co-immunoprecipitation (RAX-PKR); protein synthesis measurement; cell death assay; PKR null fibroblasts The Journal of biological chemistry High 16574643
2008 Rax has a cell-autonomous requirement in the formation of the neuroretina, retinal pigment epithelium, and distal optic stalk, as well as in posterior pituitary formation: in embryonic chimeras, Rx-deficient cells are excluded from these tissues and segregate from wild-type cells before morphogenesis begins. Embryonic chimera analysis (wild-type and Rx-/- cells); cell fate tracing PloS one Medium 19229337
2008 Otx2 and Sox2 are direct upstream regulators of Rax (Rx1): endogenous Otx2 and Sox2 proteins bind to a conserved noncoding sequence (CNS1) ~2 kb upstream of the Rax promoter, and Otx2/Sox2 synergistically activate Rax transcription via CNS1. The Otx2-Sox2 physical interaction is disrupted by Sox2 missense mutations found in ocular malformation patients. ChIP assay for Otx2/Sox2 binding to CNS1; reporter assay for transcriptional activation; co-immunoprecipitation of Otx2-Sox2 interaction; analysis of patient-derived Sox2 mutations Proceedings of the National Academy of Sciences of the United States of America High 18385377
2011 The RAX homeoprotein interacts with the EELPOT enhancer (~500 bp conserved element) of Otx2 to transactivate Otx2 mainly in the final cell cycle of retinal progenitors; conditional inactivation of Rax in vivo causes downregulation of Otx2 expression. NOTCH-HES signaling negatively regulates EELPOT to suppress Otx2, placing RAX and NOTCH-HES in opposing regulatory inputs on photoreceptor cell fate determination. Identification of Otx2 enhancer (EELPOT); luciferase reporter assay; conditional Rax knockout mice; in vivo Otx2 expression analysis The Journal of neuroscience : the official journal of the Society for Neuroscience High 22090505
2012 RAX/PACT interacts with the SUMO E2 ligase Ubc9, stimulates p53-Ubc9 association, and promotes reversible p53 sumoylation on lysine 386; RAX/PACT expression increases p53 stability and activity. Co-expression of p53 with RAX/PACT or PKR promotes G1 arrest, which is abrogated by sumoylation-deficient p53(K386R) or the desumoylase SENP1, and requires PKR kinase activity. Co-immunoprecipitation (RAX-Ubc9, p53-Ubc9); cell cycle analysis (flow cytometry); dominant-negative PKR; p53(K386R) mutant; SENP1 overexpression; p53 stability and target gene expression assays Cell cycle (Georgetown, Tex.) Medium 22214662
2013 Rax functions as a selector gene for mediobasal hypothalamic (arcuate and ventromedial hypothalamic nucleus) cell types: conditional ablation of Rax in VMH progenitors causes a fate switch from VMH neuronal phenotype to hypothalamic non-VMH identity; broader elimination using Six3::Cre leads to severe loss of both VMH and ARC cellular phenotypes. Conditional knockout mice (Shh::Cre and Six3::Cre drivers); genetic fate mapping; immunohistochemistry for hypothalamic cell-type markers The Journal of neuroscience : the official journal of the Society for Neuroscience Medium 23283339
2014 Rax is required for hypothalamic tanycyte and ependymal cell differentiation and maintenance of the cerebrospinal fluid–hypothalamus barrier: Rax haploinsufficient mice show thinning of the third ventricular wall, reduction in tanycyte and ependymal markers, ectopic ependymal cells in the α2 tanycytic zone, and reduced Evans Blue tracer diffusion from the ventricle to hypothalamic parenchyma. Rax haploinsufficient mouse generation; immunohistochemistry for tanycyte/ependymal markers; Evans Blue tracer diffusion assay The Journal of comparative neurology Medium 23939786
2015 Rax cooperates with Crx to transactivate Rhodopsin and cone opsin promoters; Rax and Crx colocalize in maturing photoreceptors and physically interact (co-immunoprecipitation); conditional knockout of Rax in postnatal photoreceptors reduces rod and cone photoreceptor gene expression and leads to specific loss of cone cells, demonstrating that Rax regulates photoreceptor maturation and cone survival. Conditional knockout (tamoxifen-inducible Rax iCKO mice); luciferase reporter assay (Rhodopsin and cone opsin promoters with Rax and Crx); co-immunoprecipitation of Rax and Crx Molecular and cellular biology High 25986607
2006 Xhmgb3 (high mobility group B3) is a downstream transcriptional target of Xenopus rax required for cell proliferation in the developing eye and brain: rax overexpression upregulates Xhmgb3, ChIP shows Xhmgb3 is recruited to the c-myc promoter to enhance c-myc transcription, and morpholino-mediated knockdown of Xhmgb3 reduces eye and brain sizes. Gene expression analysis; morpholino knockdown; ChIP assay (Xhmgb3 at c-myc promoter); overexpression in Xenopus embryos Developmental biology Medium 16445903
2011 Rx function is required for retinal regeneration in Xenopus: following partial retinal resection, Rx is re-expressed in retinal progenitor cells repopulating the wound; shRNA-mediated silencing of Rx impairs retinal regeneration including defects in wound-repopulating cells and RPE, and these defects are rescued by exogenous Rx. Partial retinal resection; shRNA silencing of Rx in vivo; rescue with exogenous Rx; marker analysis of regenerating RPCs Developmental biology Medium 21334323
2015 RAX negatively regulates PKR in postnatal anterior pituitary development: rax-/- mice show anterior pituitary hypoplasia which is rescued by ablating PKR expression or by a kinase-inactive PKR(K271R) mutant, demonstrating that PKR kinase activity mediates the rax-/- developmental defect. Reduction of RAX expression in anterior pituitary cells in vitro increases PKR activity and p21(WAF1/CIP1) expression. rax-/- × pkr-/- double knockout mice; rax-/- × PKR(K271R) knock-in mice; rax-/- × eIF2α(S51A) heterozygous mice; in vitro RAX siRNA knockdown in pituitary cells with PKR activity and p21 expression readouts The FEBS journal High 26414443
2016 Rax is required for early hypothalamic patterning: conditional inactivation of Rax prior to E8.5 causes underdevelopment of the hypothalamic neuroepithelium, impairs neurogenesis, and prevents expression of dorsomedial hypothalamic markers (POMC, Somatostatin), while ventromedial/infundibular gene expression domains expand dorsally. Loss of Rax also causes downregulation of Shh in the dorsomedial hypothalamus, and Rax and Shh are co-expressed in the rostral forebrain at late head-fold stages. Conditional Rax knockout (tamoxifen-inducible, prior to E8.5); in situ hybridization and immunohistochemistry for hypothalamic markers and Shh; comparison with Shh conditional knockout phenotype Developmental biology Medium 27212025
2008 RAX (the PKR activator, not the retinal homeobox gene) is required for normal fly neuronal development and mouse embryogenesis: Drosophila dRax mutant embryos show abnormal commissural axon structure of the CNS and lethality/sterility; mice homozygous for deletion of the entire Rax gene (exons 1–8) are not obtained at E3.5, 7, or 14, indicating preimplantation lethality, consistent with Rax expression in preimplantation blastocysts. Drosophila transposon insertion mutant analysis; mouse homozygous knockout generation attempt; embryo genotyping at multiple timepoints Mechanisms of development Medium 18634873
2014 miR-29b mediates ethanol neurotoxicity through the SP1/RAX/PKR cascade: ethanol suppresses miR-29b, which relieves repression of SP1 and thereby upregulates RAX, leading to PKR activation and neuronal apoptosis in developing cerebellar granule neurons. Overexpression of miR-29b protects neurons against ethanol-induced apoptosis. miR-29b overexpression; ethanol treatment of cerebellar granule neurons; SP1/RAX/PKR expression analysis; apoptosis assay The Journal of biological chemistry Medium 24554719
2021 Rax+ tanycytes in the median eminence are largely quiescent but enter the cell cycle upon neural injury for self-renewal and regeneration; IGF1R signaling in tanycytes is required for tissue repair under injury conditions. Oncogenic Braf activation transforms Rax+ tanycytes into proliferating tumor cells that develop into papillary craniopharyngioma-like tumors. Rax-CreERT2 fate mapping; BrdU/EdU cell-cycle analysis after neural injury; conditional Igf1r knockout in Rax+ cells; conditional Braf oncogene activation in Rax+ tanycytes; histological analysis Nature communications Medium 33863883
2018 Rx is required in retinal progenitor cells for both proliferation and cone photoreceptor fate specification: conditional deletion of Rx using the Pax6α-Cre driver leads to loss of retinal lamination, depletion of retinal progenitors (reduced BrdU labeling indicating early cell cycle exit), absence of late-born neurons (rods, bipolar cells) and Müller glia, and a specific reduction of cone photoreceptors even among early-born cells. Conditional Rx knockout (Pax6α-Cre driver); BrdU labeling; immunohistochemistry for cell-type markers at embryonic and postnatal ages Mechanisms of development Medium 29665410

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 The Rx homeobox gene is essential for vertebrate eye development. Nature 577 9177348
1999 The Rx gene from potato controls separate virus resistance and cell death responses. The Plant cell 431 10330465
2000 rax, Hes1, and notch1 promote the formation of Müller glia by postnatal retinal progenitor cells. Neuron 423 10839357
1997 rax, a novel paired-type homeobox gene, shows expression in the anterior neural fold and developing retina. Proceedings of the National Academy of Sciences of the United States of America 317 9096350
2002 Constitutive gain-of-function mutants in a nucleotide binding site-leucine rich repeat protein encoded at the Rx locus of potato. The Plant journal : for cell and molecular biology 260 12383085
2005 Generation of Rx+/Pax6+ neural retinal precursors from embryonic stem cells. Proceedings of the National Academy of Sciences of the United States of America 259 16076961
2023 Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer's disease: a phase 1b, randomized, placebo-controlled trial. Nature medicine 237 37095250
1999 RAX, a cellular activator for double-stranded RNA-dependent protein kinase during stress signaling. The Journal of biological chemistry 201 10336432
2008 The coiled-coil and nucleotide binding domains of the Potato Rx disease resistance protein function in pathogen recognition and signaling. The Plant cell 194 18344282
2006 Distinct domains in the ARC region of the potato resistance protein Rx mediate LRR binding and inhibition of activation. The Plant cell 183 16844906
2003 Mutations in the human RAX homeobox gene in a patient with anophthalmia and sclerocornea. Human molecular genetics 171 14662654
2007 Physical association of the NB-LRR resistance protein Rx with a Ran GTPase-activating protein is required for extreme resistance to Potato virus X. The Plant cell 148 17526750
2004 Regulation of vertebrate eye development by Rx genes. The International journal of developmental biology 142 15558469
2007 Structural and functional analysis of SGT1 reveals that its interaction with HSP90 is required for the accumulation of Rx, an R protein involved in plant immunity. The Plant cell 135 18032631
1999 Expression of three Rx homeobox genes in embryonic and adult zebrafish. Mechanisms of development 126 10473141
2010 RanGAP2 mediates nucleocytoplasmic partitioning of the NB-LRR immune receptor Rx in the Solanaceae, thereby dictating Rx function. The Plant cell 119 21169509
2011 An essential role for RAX homeoprotein and NOTCH-HES signaling in Otx2 expression in embryonic retinal photoreceptor cell fate determination. The Journal of neuroscience : the official journal of the Society for Neuroscience 109 22090505
2007 A RanGAP protein physically interacts with the NB-LRR protein Rx, and is required for Rx-mediated viral resistance. The Plant journal : for cell and molecular biology 104 17655649
2000 Function of Rx, but not Pax6, is essential for the formation of retinal progenitor cells in mice. Genesis (New York, N.Y. : 2000) 91 11105055
2013 Structural basis for the interaction between the potato virus X resistance protein (Rx) and its cofactor Ran GTPase-activating protein 2 (RanGAP2). The Journal of biological chemistry 89 24194517
2008 Molecular links among the causative genes for ocular malformation: Otx2 and Sox2 coregulate Rax expression. Proceedings of the National Academy of Sciences of the United States of America 85 18385377
2000 Regulation of eye formation by the Rx and pax6 homeobox genes. Cellular and molecular life sciences : CMLS 83 10766016
2011 Expression and cellular localization of microRNA-29b and RAX, an activator of the RNA-dependent protein kinase (PKR), in the retina of streptozotocin-induced diabetic rats. Molecular vision 80 21897745
2021 Antisense Inhibition of Angiotensinogen With IONIS-AGT-LRx: Results of Phase 1 and Phase 2 Studies. JACC. Basic to translational science 75 34222719
2004 Specification of the retinal fate of mouse embryonic stem cells by ectopic expression of Rx/rax, a homeobox gene. Molecular and cellular biology 72 15121868
2001 The eyeless mouse mutation (ey1) removes an alternative start codon from the Rx/rax homeobox gene. Genesis (New York, N.Y. : 2000) 72 11668677
2006 RAX, the PKR activator, sensitizes cells to inflammatory cytokines, serum withdrawal, chemotherapy, and viral infection. Blood 69 16861340
2001 Ceramide regulates protein synthesis by a novel mechanism involving the cellular PKR activator RAX. The Journal of biological chemistry 69 11148216
2012 Resolvin E1 (RX-10001) reduces corneal epithelial barrier disruption and protects against goblet cell loss in a murine model of dry eye. Cornea 68 22257864
2012 An essential role for Rax in retina and neuroendocrine system development. Development, growth & differentiation 65 22524605
2010 Mutational screening of CHX10, GDF6, OTX2, RAX and SOX2 genes in 50 unrelated microphthalmia-anophthalmia-coloboma (MAC) spectrum cases. The British journal of ophthalmology 64 20494911
2013 Rax is a selector gene for mediobasal hypothalamic cell types. The Journal of neuroscience : the official journal of the Society for Neuroscience 62 23283339
1998 Isolation of a Drosophila homolog of the vertebrate homeobox gene Rx and its possible role in brain and eye development. Proceedings of the National Academy of Sciences of the United States of America 62 9482887
2014 Rax regulates hypothalamic tanycyte differentiation and barrier function in mice. The Journal of comparative neurology 61 23939786
2013 A variant of LEAFY reveals its capacity to stimulate meristem development by inducing RAX1. The Plant journal : for cell and molecular biology 61 23445516
2004 Serine 18 phosphorylation of RAX, the PKR activator, is required for PKR activation and consequent translation inhibition. The Journal of biological chemistry 58 15299031
1999 Identification of chick rax/rx genes with overlapping patterns of expression during early eye and brain development. Mechanisms of development 55 10415362
2014 MicroRNA-29b regulates ethanol-induced neuronal apoptosis in the developing cerebellum through SP1/RAX/PKR cascade. The Journal of biological chemistry 54 24554719
2014 Rax-CreERT2 knock-in mice: a tool for selective and conditional gene deletion in progenitor cells and radial glia of the retina and hypothalamus. PloS one 54 24699247
2021 Design and Rationale of the Global Phase 3 NEURO-TTRansform Study of Antisense Oligonucleotide AKCEA-TTR-LRx (ION-682884-CS3) in Hereditary Transthyretin-Mediated Amyloid Polyneuropathy. Neurology and therapy 53 33638113
2014 Molecular epidemiology and virulence of Escherichia coli O16:H5-ST131: comparison with H30 and H30-Rx subclones of O25b:H4-ST131. International journal of medical microbiology : IJMM 52 25455219
2002 RX 821002 as a tool for physiological investigation of alpha(2)-adrenoceptors. CNS drug reviews 51 12177687
2015 Rax Homeoprotein Regulates Photoreceptor Cell Maturation and Survival in Association with Crx in the Postnatal Mouse Retina. Molecular and cellular biology 50 25986607
2019 Antisense Inhibition of Glucagon Receptor by IONIS-GCGRRx Improves Type 2 Diabetes Without Increase in Hepatic Glycogen Content in Patients With Type 2 Diabetes on Stable Metformin Therapy. Diabetes care 45 30765435
2022 A 10-step framework for use of read-across (RAX) in next generation risk assessment (NGRA) for cosmetics safety assessment. Regulatory toxicology and pharmacology : RTP 43 34990780
2012 The RAX/PACT-PKR stress response pathway promotes p53 sumoylation and activation, leading to G₁ arrest. Cell cycle (Georgetown, Tex.) 41 22214662
2006 The ascidian homolog of the vertebrate homeobox gene Rx is essential for ocellus development and function. Differentiation; research in biological diversity 40 16759288
2020 Biodegradability of di-(2-ethylhexyl) phthalate by a newly isolated bacterium Achromobacter sp. RX. The Science of the total environment 39 33035973
2014 Temporal trends in antimicrobial resistance and virulence-associated traits within the Escherichia coli sequence type 131 clonal group and its H30 and H30-Rx subclones, 1968 to 2012. Antimicrobial agents and chemotherapy 39 25199783
2012 ACE I/D and ACTN3 R/X polymorphisms as potential factors in modulating exercise-related phenotypes in older women in response to a muscle power training stimuli. Age (Dordrecht, Netherlands) 39 22855367
2010 A conserved cluster of three PRD-class homeobox genes (homeobrain, rx and orthopedia) in the Cnidaria and Protostomia. EvoDevo 39 20849646
2021 Hypothalamic Rax+ tanycytes contribute to tissue repair and tumorigenesis upon oncogene activation in mice. Nature communications 38 33863883
2018 Antisense Inhibition of Protein Tyrosine Phosphatase 1B With IONIS-PTP-1BRx Improves Insulin Sensitivity and Reduces Weight in Overweight Patients With Type 2 Diabetes. Diabetes care 37 29439147
2015 Topical delivery of aqueous micellar resolvin E1 analog (RX-10045). International journal of pharmaceutics 36 26706439
2009 Cell-autonomous requirement for rx function in the mammalian retina and posterior pituitary. PloS one 36 19229337
2008 Confirmation of RAX gene involvement in human anophthalmia. Clinical genetics 36 18783408
2004 Rax1, a protein required for the establishment of the bipolar budding pattern in yeast. Gene 36 14980713
2012 Derivation of human differential photoreceptor-like cells from the iris by defined combinations of CRX, RX and NEUROD. PloS one 34 22558175
2010 ACE I/D and ACTN3 R/X polymorphisms and muscle function and muscularity of older Caucasian men. European journal of applied physiology 34 20069311
1990 The risks and benefits of an Rx-to-OTC switch. The case of over-the-counter H2-blockers. Medical care 34 1976142
2015 A Novel Anti-Cancer Agent, 1-(3,5-Dimethoxyphenyl)-4-[(6-Fluoro-2-Methoxyquinoxalin-3-yl)Aminocarbonyl] Piperazine (RX-5902), Interferes With β-Catenin Function Through Y593 Phospho-p68 RNA Helicase. Journal of cellular biochemistry 33 25649741
2011 The Retinal Homeobox (Rx) gene is necessary for retinal regeneration. Developmental biology 33 21334323
2019 First-in-Class Phosphorylated-p68 Inhibitor RX-5902 Inhibits β-Catenin Signaling and Demonstrates Antitumor Activity in Triple-Negative Breast Cancer. Molecular cancer therapeutics 31 31488700
2013 Metabolism, mechanism of action and sensitivity profile of fluorocyclopentenylcytosine (RX-3117; TV-1360). Investigational new drugs 31 24048768
2008 In vivo and in vitro effects of a HIF-1alpha inhibitor, RX-0047. Journal of cellular biochemistry 31 18275063
2006 Interaction between RAX and PKR modulates the effect of ethanol on protein synthesis and survival of neurons. The Journal of biological chemistry 31 16574643
2016 Essential function of the transcription factor Rax in the early patterning of the mammalian hypothalamus. Developmental biology 30 27212025
2008 The Rx gene confers resistance to a range of potexviruses in transgenic Nicotiana plants. Molecular plant-microbe interactions : MPMI 30 18700820
1995 Does [3H]2-methoxy-idazoxan (RX 821002) detect more alpha-2-adrenoceptor agonist high-affinity sites than [3H]rauwolscine? A comparison of nine tissues and cell lines. The Journal of pharmacology and experimental therapeutics 29 7791100
2019 IONIS-PKKRx a Novel Antisense Inhibitor of Prekallikrein and Bradykinin Production. Nucleic acid therapeutics 28 30817230
2012 RAX and anophthalmia in humans: evidence of brain anomalies. Molecular vision 27 22736936
2004 Phenotype and X inactivation in 45,X/46,X,r(X) cases. American journal of medical genetics. Part A 27 15216549
1999 The effect of an Rx-to-OTC switch on medication prescribing patterns and utilization of physician services: the case of H2-receptor antagonists. Medical care 27 10213023
2020 RX-5902, a novel β-catenin modulator, potentiates the efficacy of immune checkpoint inhibitors in preclinical models of triple-negative breast Cancer. BMC cancer 26 33148223
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
2005 Microdeletion in the SHOX 3' region associated with skeletal phenotypes of Langer mesomelic dysplasia in a 45,X/46,X,r(X) infant and Leri-Weill dyschondrosteosis in her 46,XX mother: implication for the SHOX enhancer. American journal of medical genetics. Part A 26 16007631
2011 Repression of Rx gene on the left side of the sensory vesicle by Nodal signaling is crucial for right-sided formation of the ocellus photoreceptor in the development of Ciona intestinalis. Developmental biology 25 21402066
2011 Rax : developmental and daily expression patterns in the rat pineal gland and retina. Journal of neurochemistry 25 21749377
2006 The Rx-like homeobox gene (Rx-L) is necessary for normal photoreceptor development. Investigative ophthalmology & visual science 25 17003412
2016 The Cytidine Analog Fluorocyclopentenylcytosine (RX-3117) Is Activated by Uridine-Cytidine Kinase 2. PloS one 24 27612203
2014 Xenopus mutant reveals necessity of rax for specifying the eye field which otherwise forms tissue with telencephalic and diencephalic character. Developmental biology 24 25224223
2013 Full prescription coverage versus usual prescription coverage after coronary artery bypass graft surgery: analysis from the post-myocardial infarction free Rx event and economic evaluation (FREEE) randomized trial. Circulation 24 24030410
2008 RAX is required for fly neuronal development and mouse embryogenesis. Mechanisms of development 24 18634873
2006 Nucleosome regulator Xhmgb3 is required for cell proliferation of the eye and brain as a downstream target of Xenopus rax/Rx1. Developmental biology 23 16445903
2024 CRISPR/dCas13(Rx) Derived RNA N6-methyladenosine (m6A) Dynamic Modification in Plant. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 22 39229923
2019 RX-3117 (fluorocyclopentenyl cytosine): a novel specific antimetabolite for selective cancer treatment. Expert opinion on investigational drugs 22 30879349
1987 Characterization of alpha 2-adrenergic receptors of calf retina membranes by [3H]-rauwolscine and [3H]-RX 781094 binding. Biochemical pharmacology 22 3038126
2010 Multiple coat protein mutations abolish recognition of Pepino mosaic potexvirus (PepMV) by the potato rx resistance gene in transgenic tomatoes. Molecular plant-microbe interactions : MPMI 21 20192825
2015 Genomic and Functional Portrait of a Highly Virulent, CTX-M-15-Producing H30-Rx Subclone of Escherichia coli Sequence Type 131. Antimicrobial agents and chemotherapy 20 26195517
2011 Onecut is a direct neural-specific transcriptional activator of Rx in Ciona intestinalis. Developmental biology 20 21600895
2009 Sequence alterations in RX in patients with microphthalmia, anophthalmia, and coloboma. Molecular vision 20 19158959
2009 The fractionated orthology of Bs2 and Rx/Gpa2 supports shared synteny of disease resistance in the Solanaceae. Genetics 20 19474202
2018 The role of the Rx homeobox gene in retinal progenitor proliferation and cell fate specification. Mechanisms of development 19 29665410
2015 The protein activator of protein kinase R, PACT/RAX, negatively regulates protein kinase R during mouse anterior pituitary development. The FEBS journal 18 26414443
2014 A novel cytidine analog, RX-3117, shows potent efficacy in xenograft models, even in tumors that are resistant to gemcitabine. Anticancer research 18 25503121
1983 ACTH-(1-24) and RX 336-M induce excessive grooming in rats through different mechanisms. European journal of pharmacology 18 6305675
2021 Resveratrol inhibits neural apoptosis and regulates RAX/P-PKR expression in retina of diabetic rats. Nutritional neuroscience 17 34693895
2017 Whole genome sequencing, molecular typing and in vivo virulence of OXA-48-producing Escherichia coli isolates including ST131 H30-Rx, H22 and H41 subclones. Scientific reports 17 28935873
2015 Deficient PKR in RAX/PKR Association Ameliorates Ethanol-Induced Neurotoxicity in the Developing Cerebellum. Cerebellum (London, England) 16 25592072
2005 Conditional alleles for activation and inactivation of the mouse Rx homeobox gene. Genesis (New York, N.Y. : 2000) 16 15789424

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