Affinage

MYRF

Myelin regulatory factor · UniProt Q9Y2G1

Length
1151 aa
Mass
124.4 kDa
Annotated
2026-06-10
96 papers in source corpus 24 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MYRF is a membrane-anchored transcription factor that governs terminal differentiation programs across multiple tissues by coupling regulated proteolysis to gene activation (PMID:23966833, PMID:23966832, PMID:28441531). Synthesized as an ER/membrane-associated protein, MYRF undergoes constitutive, cell-type-independent autoproteolytic self-cleavage that liberates a nuclear-targeted N-terminal fragment from its transmembrane C-terminal region (PMID:23966833, PMID:23966832). Cleavage is catalyzed by a bacteriophage tailspike-related intramolecular chaperone (ICA) domain whose triple-helical coiled-coil drives trimerization, and self-cleavage proceeds through a serine-lysine catalytic dyad that is active only when ICA domains are organized as trimers (PMID:23966832, PMID:34345217). The released N-terminal fragments themselves assemble into stable homo-trimers, and this homo-trimerization both is essential for function and defines DNA-binding specificity, enabling recognition of a homo-trimeric DNA motif at enhancers of oligodendrocyte and myelin genes (PMID:23966833, PMID:23966832, PMID:28160598). Transcriptional activity resides in an N-terminal-most transactivation domain that is repressed by SUMOylation at K276 without affecting stability or nuclear localization (PMID:30166609). In the myelinating lineage, Sox10 induces Myrf and the two factors physically interact to co-activate differentiation genes while MYRF also restrains Sox10-dependent OPC-stage genes, producing a bimodal switch into maturation (PMID:24204311, PMID:31828317, PMID:27532821). MYRF activation is held in check at the membrane: the ER transmembrane protein TMEM98 binds the MYRF C-terminus to inhibit self-cleavage and nuclear translocation, controlling outcomes such as RPE integrity and eye size (PMID:30249802, PMID:32236127), while the released N-terminal fragment is targeted for degradation by GSK-3-primed, SCF-FBXW7-mediated ubiquitylation to balance myelin growth and homeostasis (PMID:29472293, PMID:40841354). Beyond myelination, MYRF directs mesothelial specification synergistically with YAP/TAZ, with early loss causing congenital diaphragmatic hernia (PMID:41558485), and is required for epicardial development [PMID:bio_10.1101_2025.10.17.682841]. Disease-associated DNA-binding-domain missense mutations abolish transcriptional activity by disrupting homo-trimerization, acting through haploinsufficiency or dominant-negative mechanisms (PMID:33798553).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 2013 High

    Established the core paradigm that MYRF is a membrane-tethered transcription factor activated by autoproteolytic release of a nuclear DNA-binding fragment, answering how an ER-associated protein controls myelin gene transcription.

    Evidence Biochemical fractionation, ChIP-Seq, domain mutagenesis and reporter assays in two simultaneous studies

    PMID:23966832 PMID:23966833

    Open questions at the time
    • Did not resolve the structural basis of cleavage
    • Trigger/regulation of cleavage timing unknown
  2. 2013 High

    Identified the bacteriophage tailspike-related ICA chaperone domain as the trimerization and self-cleavage module, explaining the catalytic mechanism behind activation and showing it is constitutive and tissue-independent.

    Evidence Bioinformatics and reconstitution in E. coli and yeast plus functional transcriptional assays

    PMID:23966832

    Open questions at the time
    • Catalytic residues not yet defined structurally
    • How cleavage is regulated in vivo if constitutive in heterologous systems
  3. 2013 High

    Placed MYRF downstream of and in physical partnership with Sox10, defining the transcriptional circuit that drives oligodendrocyte differentiation.

    Evidence Enhancer/reporter mapping, Co-IP, and luciferase synergy assays with in vivo genetics

    PMID:24204311

    Open questions at the time
    • Direct vs indirect mechanism of synergy not resolved here
    • Stoichiometry of MYRF-Sox10 complex unknown
  4. 2016 Medium

    Clarified that MYRF binds DNA as a trimer while Sox10 binds as a monomer and that cooperation occurs after binding, refining the biochemical logic of co-activation.

    Evidence ChIP, EMSA, promoter reporter assays and shRNA knockdown in oligodendroglial cells

    PMID:27532821

    Open questions at the time
    • Post-binding cooperative step molecularly undefined
    • Single target gene (Dusp15) analyzed
  5. 2017 High

    Showed the N-terminal fragment functions as a homo-trimer that itself dictates DNA-binding specificity, converting the trimerization requirement into a sequence-recognition mechanism via a homo-trimeric DNA motif.

    Evidence Gel filtration, mutagenesis, C. elegans rescue and DNA motif analysis

    PMID:28160598

    Open questions at the time
    • Structure of fragment-DNA complex not determined
    • Region driving N-fragment trimerization mapped only approximately
  6. 2017 High

    Demonstrated conservation of the membrane-cleavage-nuclear translocation mechanism in C. elegans and extended MYRF function beyond myelination to synaptic rewiring.

    Evidence Live imaging of GFP fusions, cleavage assays, loss- and gain-of-function in C. elegans

    PMID:28441531

    Open questions at the time
    • Direct target genes for rewiring not identified here
    • What triggers stage-specific cleavage unknown
  7. 2018 High

    Identified TMEM98 as a C-terminus-binding inhibitor of MYRF self-cleavage, providing a negative feedback brake on activation during oligodendrocyte differentiation.

    Evidence Reciprocal Co-IP, overexpression in chicken spinal cord, cleavage and nuclear translocation assays

    PMID:30249802

    Open questions at the time
    • Structural basis of inhibition unknown
    • Whether TMEM98 release is signal-regulated unresolved
  8. 2018 High

    Established a degradation arm of MYRF control whereby GSK-3 phosphorylation of a phosphodegron licenses SCF-FBXW7 to ubiquitylate MYRF, adding post-cleavage turnover regulation.

    Evidence Co-IP, in vitro ubiquitylation with recombinant SCF-FBXW7, phosphodegron mutagenesis, GSK-3 inhibition

    PMID:29472293

    Open questions at the time
    • In vivo significance not yet shown at this stage
    • Which MYRF fragment is the primary substrate not fully resolved
  9. 2018 Medium

    Localized transcriptional activity to an N-terminal transactivation domain and showed SUMOylation at K276 represses it independently of stability/localization, identifying a tunable activity setpoint.

    Evidence Gal4 fusion reporter assays and site-directed sumoylation-site mutagenesis

    PMID:30166609

    Open questions at the time
    • SUMO ligase/conditions in vivo not identified
    • No structural validation
  10. 2019 Medium

    Linked MYRF to retinal pigment epithelium maintenance and showed a regulatory relationship with TMEM98 (physical interaction plus MYRF control of Tmem98 expression).

    Evidence Co-IP and conditional Myrf knockout mouse with histological/molecular phenotyping

    PMID:31048900

    Open questions at the time
    • Direct vs indirect regulation of Tmem98 unresolved
    • Mechanism of RPE degeneration not dissected
  11. 2020 High

    Confirmed in vivo that TMEM98 restrains MYRF activation, with loss causing ectopic MYRF nuclear localization and altered eye size, validating the membrane brake physiologically.

    Evidence BioID proximity labeling and RPE-specific Tmem98 conditional knockout mice with localization and cleavage assays

    PMID:32236127

    Open questions at the time
    • Downstream MYRF targets controlling eye size unidentified
    • Signal that relieves inhibition unknown
  12. 2020 High

    Defined a bimodal regulatory logic in which MYRF co-activates differentiation genes with Sox10 yet sequesters Sox10 to repress OPC-stage genes, explaining the differentiation switch.

    Evidence ChIP, EMSA, reporter assays, Co-IP and loss-of-function analysis

    PMID:31828317

    Open questions at the time
    • Quantitative thresholds for switch behavior undefined
    • Generality across all Sox10 targets untested
  13. 2020 Medium

    Extended MYRF function to non-neural epithelia, showing HNF1B-driven MYRF regulates secretory protein expression to prevent ER overload in pancreatic ductal adenocarcinoma.

    Evidence Conditional MYRF knockout in PDAC cells, RNA-seq, spheroid and in vivo tumor models

    PMID:32997974

    Open questions at the time
    • Direct MYRF target genes in PDAC not enumerated
    • Whether the proteolytic mechanism operates identically here untested
  14. 2021 High

    Provided the crystal structure of the ICA domain plus stalk, showing the C-terminal coiled-coil drives trimerization and that the serine-lysine dyad self-cleaves only in the trimeric state, giving an atomic basis for activation control.

    Evidence X-ray crystallography at 2.4 Angstrom with catalytic-residue mutagenesis

    PMID:34345217

    Open questions at the time
    • Structure of full-length membrane-anchored MYRF lacking
    • Conformational change driving cleavage not captured
  15. 2021 Medium

    Showed disease-associated DBD missense mutations abolish activity by disrupting homo-trimerization, defining distinct haploinsufficient versus dominant-negative allele classes for MYRF disorders.

    Evidence Mutagenesis with transcriptional and trimerization biochemical assays and structural perturbation analysis

    PMID:33798553

    Open questions at the time
    • No patient-tissue validation in this study
    • Structural basis of dominant-negative G435R not directly visualized
  16. 2021 High

    Identified the LRR-TM protein PAN-1 as required for MYRF membrane localization in C. elegans, revealing that proper membrane targeting is a prerequisite for rewiring-controlling cleavage.

    Evidence Co-IP, live imaging and genetic epistasis in C. elegans

    PMID:33950834

    Open questions at the time
    • Whether a PAN-1 ortholog functions in vertebrates unknown
    • How PAN-1 binding influences cleavage timing not fully resolved
  17. 2022 Medium

    Connected MYRF to epigenetic regulation through physical interaction with DNMT3A, linking MYRF to DNA methylation at glaucoma-related loci.

    Evidence Co-IP, transcriptome sequencing and DNA methylation sequencing of Myrf mutant retinas

    PMID:36129575

    Open questions at the time
    • Single Co-IP without reciprocal validation in vivo
    • Causal link between methylation changes and glaucoma correlative
  18. 2024 Medium

    Demonstrated MYRF-1 directly activates the heterochronic microRNA lin-4 in C. elegans with cleavage/nuclear timing matching expression onset, positioning MYRF as a developmental timing driver.

    Evidence C. elegans loss- and gain-of-function plus live imaging of MYRF-1::GFP foci at the lin-4 promoter

    PMID:38963411

    Open questions at the time
    • Upstream signal setting cleavage timing not defined
    • Whether vertebrate MYRF has analogous miRNA targets unknown
  19. 2025 High

    Showed FBXW7 degrades the N-terminal MYRF fragment in vivo to balance myelin growth and homeostasis, establishing the physiological importance of the degradation arm in myelinating oligodendrocytes.

    Evidence Zebrafish and conditional mouse oligodendrocyte knockouts, primary OL cultures, Co-IP and degradation assays

    PMID:40841354

    Open questions at the time
    • Whether GSK-3 priming operates identically in OLs not retested here
    • Signals controlling FBXW7 access to N-MYRF unknown
  20. 2025 Medium

    Expanded MYRF developmental roles to epicardium, showing epicardial but not cardiomyocyte MYRF is required for cardiac development.

    Evidence Cell-type-specific conditional knockouts with histology and fate tracing (preprint)

    PMID:bio_10.1101_2025.10.17.682841

    Open questions at the time
    • Peer review pending
    • Direct epicardial target genes not identified
  21. 2025 Medium

    Broadened the heterochronic role to a network of microRNAs and oscillatory genes with lin-42/Period feedback, framing MYRF as a node in a developmental timing oscillator.

    Evidence C. elegans genetics, direct binding assays at miRNA promoters and oscillation imaging (preprint)

    PMID:41659655

    Open questions at the time
    • Peer review pending
    • Molecular mechanism of oscillation generation unresolved
  22. 2025 Medium

    Showed MYRF-1 directly primes linker cell death by binding the pqn-41 promoter, extending MYRF function to programmed cell death timing.

    Evidence Single-cell RNA-seq, auxin-inducible MYRF-1 degradation, promoter binding-site deletion in C. elegans (preprint)

    PMID:41427293

    Open questions at the time
    • Peer review pending
    • Conservation of cell-death role in vertebrates untested
  23. 2026 High

    Established MYRF as a driver of mesothelial specification acting synergistically with YAP/TAZ, with early loss causing congenital diaphragmatic hernia.

    Evidence Temporally controlled conditional Myrf knockouts and compound Myrf/YAP-TAZ mutants with fate analysis

    PMID:41558485

    Open questions at the time
    • Mechanism of MYRF-YAP/TAZ synergy molecularly undefined
    • Direct mesothelial target genes not enumerated
  24. 2031 Medium

    Resolved dual cis/trans inhibition of cleavage via the MYRF-1 juxtamembrane region and the PAN-1 cytoplasmic tail, defining the molecular brakes that set developmental timing of activation.

    Evidence Endogenous CRISPR editing, deletion mutants, live imaging and lin-4 reporters in C. elegans (preprint)

    PMID:41542402

    Open questions at the time
    • Peer review pending
    • Whether equivalent cis-inhibition exists in vertebrate MYRF unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The signals that trigger MYRF self-cleavage and relieve membrane inhibition in vertebrate tissues, and the full structure of the membrane-anchored holoprotein, remain undefined.
  • No activating signal for cleavage identified in mammals
  • No full-length membrane-anchored structure
  • Direct vertebrate target gene catalog incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 4 GO:0140110 transcription regulator activity 4 GO:0016787 hydrolase activity 2 GO:0044183 protein folding chaperone 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005634 nucleus 4 GO:0005783 endoplasmic reticulum 3 GO:0005886 plasma membrane 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-5357801 Programmed Cell Death 1
Partners
DNMT3AFBXW7GSK-3HNF1BPAN-1SOX10TMEM98
Complex memberships
MYRF homo-trimerSCF-FBXW7 (substrate of)

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 MYRF is synthesized as an ER/membrane-associated protein that undergoes autoproteolytic cleavage to separate its transmembrane-domain-containing C-terminal region from a nuclear-targeted N-terminal region; the N-terminal cleavage product directly binds enhancer regions of oligodendrocyte-specific and myelin genes via a defined DNA-binding consensus sequence to activate their transcription. Biochemical fractionation, ChIP-Seq, domain mutagenesis, reporter assays PLoS biology High 23966832 23966833
2013 MYRF contains a protein domain related to bacteriophage tailspike intramolecular chaperone (ICA) domains that facilitates MYRF trimerization and autoproteolytic self-cleavage; this chaperone domain-mediated autoproteolysis is essential for MYRF transcriptional activity and its ability to promote oligodendrocyte maturation. The proteolysis occurs constitutively and independent of cell- or tissue-type, as demonstrated by reconstitution in E. coli and yeast. Bioinformatics, biochemical reconstitution in E. coli and yeast, functional transcriptional assays, domain mutagenesis PLoS biology High 23966832
2013 Sox10 induces Myrf expression through a Sox10-responsive enhancer in intron 1 of the Myrf gene; once induced, Myrf physically interacts with Sox10 and they synergistically activate several myelin-specific genes. Reporter/enhancer assays, Co-immunoprecipitation (physical interaction), luciferase synergy assays, in vivo genetics PLoS genetics High 24204311
2017 MYRF N-terminal fragments assemble into stable homo-trimers before ER release; homo-trimerization is essential for the biological function of the N-terminal fragment, and the region adjacent to the DNA-binding domain is pivotal for homo-trimerization. Homo-trimerization defines the DNA-binding specificity of Myrf N-terminal fragments, enabling binding to a novel homo-trimeric DNA motif. Biochemical fractionation, gel filtration, mutagenesis, C. elegans genetic rescue, computational DNA motif analysis Nucleic acids research High 28160598
2018 TMEM98, an ER-associated transmembrane protein, physically binds to the C-terminal region of MYRF and inhibits its self-cleavage and N-fragment nuclear translocation, thereby acting as a negative feedback regulator of MYRF activity during oligodendrocyte differentiation. Co-immunoprecipitation, overexpression in embryonic chicken spinal cord, Western blot for cleavage products, nuclear translocation assays The Journal of neuroscience High 30249802
2020 TMEM98 inhibits the autoproteolytic self-cleavage of MYRF; in retinal pigment epithelium lacking TMEM98, MYRF is ectopically activated and abnormally localised to nuclei, demonstrating that TMEM98–MYRF interaction controls MYRF activation state and eye size. Proximity labeling (BioID) to identify interacting partners, conditional Tmem98 knockout mice (RPE-specific), immunofluorescence for MYRF nuclear localization, cleavage assays PLoS genetics High 32236127
2018 The SCF-FBXW7 E3 ubiquitin ligase complex directly binds the NH2-terminal cytoplasmic domain of MYRF and polyubiquitylates it in an in vitro ubiquitylation assay; GSK-3 kinase phosphorylates a putative phosphodegron in MYRF, and this phosphorylation is required for FBXW7-mediated degradation of MYRF. Co-immunoprecipitation, in vitro ubiquitylation assay with recombinant SCF-FBXW7, phosphodegron mutagenesis, GSK-3 inhibitor treatment The Journal of biological chemistry High 29472293
2025 FBXW7 directly binds and degrades the N-terminal fragment of MYRF (N-MYRF) to control the balance between oligodendrocyte myelin growth and homeostasis; loss of Fbxw7 in myelinating oligodendrocytes increases myelin sheath lengths and causes progressive myelin abnormalities including outfolds and ectopic ensheathment. Zebrafish genetics, conditional mouse KO in oligodendrocytes, primary OL cultures, biochemical Co-IP and degradation assays Nature communications High 40841354
2020 Myrf cooperates with Sox10 in a bimodal manner: it co-activates differentiation genes by joint binding with Sox10 to the same regulatory regions, and it inhibits Sox10-dependent activation of OPC-stage genes by physical interaction with Sox10 leading to Sox10 sequestration on genes lacking Myrf binding sites. ChIP, EMSA, reporter assays, Co-immunoprecipitation, loss-of-function analysis Nucleic acids research High 31828317
2018 The N-terminal-most (NTM) domain of Myrf functions as its transactivation domain; when fused to Gal4 it activates transcription independently of trimerization. This NTM domain can be sumoylated at three lysine residues (K123, K208, K276), with K276 as the main acceptor; K276 sumoylation represses the transactivation function without affecting Myrf stability or nuclear localization. Gal4 fusion reporter assays, site-directed mutagenesis of sumoylation sites, Western blot, nuclear localization assays Scientific reports Medium 30166609
2021 Four disease-associated MYRF DNA-binding domain missense mutations (F387S, Q403H, G435R, L479V) abolish transcriptional activity by disrupting homo-trimerization through perturbation of DBD structure. Three mutations (F387S, Q403H, L479V) are tolerated as single copies within a homo-trimer (haploinsufficiency mechanism), while G435R acts as a dominant negative. Mutagenesis, transcriptional activity assays, trimerization biochemical assays, structural perturbation analysis The Journal of biological chemistry Medium 33798553
2021 Crystal structure of the MyRF ICA domain with its upstream β-helical stalk (at 2.4 Å) reveals that a triple α-helical coiled-coil at the ICA domain C-terminus is the main driving force for trimerization; self-cleavage occurs via a conserved serine-lysine catalytic dyad and is activated only when ICA domains are organized as trimers. X-ray crystallography, structural analysis, mutagenesis of catalytic residues International journal of biological sciences High 34345217
2017 In C. elegans, the MYRF family members MYRF-1 and MYRF-2 localize to the ER membrane, undergo proteolytic cleavage to release active N-terminal fragments that translocate to the nucleus, and cooperatively regulate synaptic rewiring; overexpression of active forms of MYRF is sufficient to accelerate synaptic rewiring. Live imaging of GFP fusions, cleavage assays, genetic loss-of-function, overexpression rescue in C. elegans Developmental cell High 28441531
2021 In C. elegans, the LRR-TM protein PAN-1 localizes on the cell membrane, physically interacts with MYRF via extracellular domains, and is required for MYRF cell membrane localization; loss of PAN-1 abolishes MYRF membrane localization and consequently blocks myrf-dependent neuronal rewiring. Co-immunoprecipitation, live imaging of localization, genetic epistasis in C. elegans loss-of-function eLife High 33950834
2019 MYRF physically interacts with TMEM98 (confirmed by Co-immunoprecipitation); Myrf conditional knockout mice develop retinal pigment epithelium depigmentation and retinal degeneration, and show reduced expression of Tmem98, indicating MYRF regulates Tmem98 expression. Co-immunoprecipitation, conditional knockout mouse model (Myrf CKO), histological and molecular phenotyping PLoS genetics Medium 31048900
2022 MYRF physically interacts with DNMT3A (demonstrated by Co-immunoprecipitation); in Myrf mutant mouse retinas, Dnmt3a is downregulated and DNA methylation patterns at glaucoma-related loci are altered, linking the MYRF–DNMT3A interaction to primary angle-closure glaucoma pathogenesis. Co-immunoprecipitation, transcriptome sequencing of Myrf mutant retinas, DNA methylation sequencing Human genetics Medium 36129575
2020 In pancreatic ductal adenocarcinoma cells, MYRF expression is controlled by the transcription factor HNF1B; MYRF acts to regulate expression of highly glycosylated, cysteine-rich secretory proteins, preventing ER overload. MYRF-deficient PDAC cells show ER stress and impaired proliferation. Conditional MYRF knockout in PDAC cells, RNA-seq, spheroid formation assay, in vivo tumor models Developmental cell Medium 32997974
2024 In C. elegans, MYRF-1 is necessary for activation of the microRNA lin-4; increased MYRF-1 cleavage and nuclear accumulation coincides with lin-4 expression timing, and hyperactive MYRF-1 can prematurely drive lin-4 expression; MYRF-1 directly binds to the lin-4 promoter as shown by nuclear GFP focus formation at the tandem lin-4 promoter. C. elegans genetics (loss-of-function and gain-of-function), live imaging of MYRF-1::GFP nuclear foci at lin-4 promoter loci, cleavage/translocation timing assays eLife Medium 38963411
2016 Sox10 and Myrf cooperatively activate Dusp15 expression through the Dusp15 promoter, which contains both a functional Sox10-binding site and a functional Myrf-binding site; Sox10 binds as a monomer while Myrf binds as a trimer; cooperative activation occurs at a step after binding rather than through facilitated binding. ChIP, EMSA, reporter/promoter assays, shRNA knockdown of Dusp15 in oligodendroglial cells Glia Medium 27532821
2031 In C. elegans, MYRF-1 cleavage is dually inhibited by (1) a juxtamembrane (JM) region of MYRF-1 that acts as a cis self-inhibitor of cleavage, and (2) the cytoplasmic tail (CCT) of PAN-1 which acts as a trans-inhibitor; deletion of either leads to premature MYRF-1 nuclear entry, early lin-4 activation, and larval lethality, establishing these as key regulators of developmental timing. Endogenous gene editing (CRISPR), C. elegans genetics (deletion mutants), live imaging of nuclear accumulation, lin-4 reporter assays bioRxivpreprint Medium 41542402
2025 In C. elegans, MYRF-1 directly activates key heterochronic microRNAs (lin-4, mir-48/241/84, let-7) and amplifies oscillatory gene networks including nhr-23; MYRF-1 nuclear accumulation oscillates across larval stages; lin-42/Period feeds back to repress myrf; loss of MYRF causes developmental arrest during late intermolt phase. C. elegans genetics, ChIP or direct binding assays for heterochronic miRNA promoters, loss-of-function with stage-arrest readout, oscillation imaging bioRxivpreprint Medium 41659655
2025 In C. elegans, MYRF-1 directly binds the promoter of pqn-41 (a polyglutamine protein gene required for linker cell death); MYRF-1 nuclear translocation in the linker cell primes linker-cell-type death early during migration; deleting a bona fide MYRF-1 binding site within pqn-41 promotes linker cell survival. Single-cell mRNA sequencing, auxin-inducible degradation of MYRF-1, promoter binding/deletion assays in C. elegans bioRxivpreprint Medium 41427293
2025 MYRF is most highly expressed in epicardial cells among cardiac cell types; conditional deletion of Myrf in epicardial cells (EPCs) causes severely degenerated epicardium, dramatically reduced epicardial-derived cells, and thin myocardial wall; deletion in cardiomyocytes produces no overt phenotype, establishing epicardial MYRF as the cell-type-specific requirement for cardiac development. Cell-type-specific conditional KO (epicardial Cre vs cardiomyocyte Cre), histological analysis, cell fate tracing bioRxivpreprint Medium bio_10.1101_2025.10.17.682841
2026 Myrf inactivation early in embryogenesis causes CDH and defective mesothelium specification in mice; later inactivation leads to enhanced mesothelial differentiation into mesenchymal cell types including elastin-expressing smooth muscle/myofibroblasts encasing the lung; MYRF functions synergistically with YAP/TAZ in mesothelium differentiation, as shown by compound mutants. Conditional Myrf knockout mice with temporally controlled Cre, compound Myrf/YAP-TAZ mutants (genetic epistasis), histological and cell fate analysis Developmental cell High 41558485
2031 In C. elegans, MYRF-1 must traffic to the cell membrane before cleavage occurs; the timing of N-MYRF release from the membrane coincides with the onset of synaptic rewiring; PAN-1 and MYRF interact via their extracellular regions on the cell membrane, and loss of PAN-1 abolishes MYRF membrane localization and blocks myrf-dependent neuronal rewiring. Live imaging of subcellular localization, Co-IP of extracellular domain interactions, C. elegans genetics eLife Medium 33950834

Source papers

Stage 0 corpus · 96 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Gametogenesis in yeast is regulated by a transcriptional cascade dependent on Ndt80. Molecular cell 304 9660952
1995 NDT80, a meiosis-specific gene required for exit from pachytene in Saccharomyces cerevisiae. Molecular and cellular biology 293 8524222
2013 MYRF is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes. PLoS biology 213 23966833
2013 The transcription factors Sox10 and Myrf define an essential regulatory network module in differentiating oligodendrocytes. PLoS genetics 184 24204311
1998 NDT80 and the meiotic recombination checkpoint regulate expression of middle sporulation-specific genes in Saccharomyces cerevisiae. Molecular and cellular biology 141 9742092
2000 The pachytene checkpoint prevents accumulation and phosphorylation of the meiosis-specific transcription factor Ndt80. Proceedings of the National Academy of Sciences of the United States of America 92 11035815
2018 De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders. PLoS genetics 89 30532227
2012 The Sum1/Ndt80 transcriptional switch and commitment to meiosis in Saccharomyces cerevisiae. Microbiology and molecular biology reviews : MMBR 84 22390969
2002 Regulation of the premiddle and middle phases of expression of the NDT80 gene during sporulation of Saccharomyces cerevisiae. Molecular and cellular biology 77 12192041
2013 A Bacteriophage tailspike domain promotes self-cleavage of a human membrane-bound transcription factor, the myelin regulatory factor MYRF. PLoS biology 61 23966832
2019 Variants in myelin regulatory factor (MYRF) cause autosomal dominant and syndromic nanophthalmos in humans and retinal degeneration in mice. PLoS genetics 60 31048900
2002 Phosphorylation and maximal activity of Saccharomyces cerevisiae meiosis-specific transcription factor Ndt80 is dependent on Ime2. Molecular and cellular biology 59 12242283
2019 Review of the phenotypic spectrum associated with haploinsufficiency of MYRF. American journal of medical genetics. Part A 58 31069960
2018 Interactive Repression of MYRF Self-Cleavage and Activity in Oligodendrocyte Differentiation by TMEM98 Protein. The Journal of neuroscience : the official journal of the Society for Neuroscience 56 30249802
2002 Structure of the sporulation-specific transcription factor Ndt80 bound to DNA. The EMBO journal 56 12411490
2017 Impact of ERG3 mutations and expression of ergosterol genes controlled by UPC2 and NDT80 in Candida parapsilosis azole resistance. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases 55 28196695
2002 Role of Ndt80, Sum1, and Swe1 as targets of the meiotic recombination checkpoint that control exit from pachytene and spore formation in Saccharomyces cerevisiae. Molecular and cellular biology 54 12192042
2011 The transcription factor Ndt80 does not contribute to Mrr1-, Tac1-, and Upc2-mediated fluconazole resistance in Candida albicans. PloS one 51 21980509
2018 De novo variants in Myelin regulatory factor (MYRF) as candidates of a new syndrome of cardiac and urogenital anomalies. American journal of medical genetics. Part A 49 29446546
2020 Myrf guides target gene selection of transcription factor Sox10 during oligodendroglial development. Nucleic acids research 46 31828317
2017 Coordination of Double Strand Break Repair and Meiotic Progression in Yeast by a Mek1-Ndt80 Negative Feedback Loop. Genetics 45 28249986
2018 MYRF is associated with encephalopathy with reversible myelin vacuolization. Annals of neurology 43 29265453
2010 Meiotic regulators Ndt80 and ime2 have different roles in Saccharomyces and Neurospora. Genetics 43 20519745
2017 Homo-trimerization is essential for the transcription factor function of Myrf for oligodendrocyte differentiation. Nucleic acids research 42 28160598
2018 Genetic Analysis of NDT80 Family Transcription Factors in Candida albicans Using New CRISPR-Cas9 Approaches. mSphere 39 30463924
2002 Crystal structure of the DNA-binding domain from Ndt80, a transcriptional activator required for meiosis in yeast. Proceedings of the National Academy of Sciences of the United States of America 39 12384578
2014 Positive feedback of NDT80 expression ensures irreversible meiotic commitment in budding yeast. PLoS genetics 38 24901499
2018 Mek1 coordinates meiotic progression with DNA break repair by directly phosphorylating and inhibiting the yeast pachytene exit regulator Ndt80. PLoS genetics 36 30496175
2015 The N-acetylglucosamine catabolic gene cluster in Trichoderma reesei is controlled by the Ndt80-like transcription factor RON1. Molecular microbiology 36 26481444
2013 A p53-like transcription factor similar to Ndt80 controls the response to nutrient stress in the filamentous fungus, Aspergillus nidulans. F1000Research 35 24358888
2011 Regulation of the C. elegans molt by pqn-47. Developmental biology 33 21989027
2008 Cdc7-Dbf4 regulates NDT80 transcription as well as reductional segregation during budding yeast meiosis. Molecular biology of the cell 32 18768747
2017 Myrf ER-Bound Transcription Factors Drive C. elegans Synaptic Plasticity via Cleavage-Dependent Nuclear Translocation. Developmental cell 31 28441531
2019 MYRF haploinsufficiency causes 46,XY and 46,XX disorders of sex development: bioinformatics consideration. Human molecular genetics 30 30985895
2019 Novel truncation mutations in MYRF cause autosomal dominant high hyperopia mapped to 11p12-q13.3. Human genetics 28 31172260
2011 The budding yeast polo-like kinase Cdc5 regulates the Ndt80 branch of the meiotic recombination checkpoint pathway. Molecular biology of the cell 26 21795394
2019 Autosomal dominant nanophthalmos and high hyperopia associated with a C-terminal frameshift variant in MYRF. Molecular vision 25 31700225
2020 The nanophthalmos protein TMEM98 inhibits MYRF self-cleavage and is required for eye size specification. PLoS genetics 23 32236127
2016 The Dual-specificity phosphatase Dusp15 is regulated by Sox10 and Myrf in Myelinating Oligodendrocytes. Glia 23 27532821
2020 Pancreatic Cancer Cells Require the Transcription Factor MYRF to Maintain ER Homeostasis. Developmental cell 21 32997974
2011 Nuclear localization of the meiosis-specific transcription factor Ndt80 is regulated by the pachytene checkpoint. Molecular biology of the cell 21 21471004
2004 Characterization of critical interactions between Ndt80 and MSE DNA defining a novel family of Ig-fold transcription factors. Nucleic acids research 18 15161958
2003 Activity of phosphoforms and truncated versions of Ndt80, a checkpoint-regulated sporulation-specific transcription factor of Saccharomyces cerevisiae. Molecular genetics and genomics : MGG 17 14605875
2000 cDNA cloning and genomic structure of a novel gene (C11orf9) localized to chromosome 11q12-->q13.1 which encodes a highly conserved, potential membrane-associated protein. Cytogenetics and cell genetics 17 10828591
2021 Functional mechanisms of MYRF DNA-binding domain mutations implicated in birth defects. The Journal of biological chemistry 15 33798553
2018 Elucidating the transactivation domain of the pleiotropic transcription factor Myrf. Scientific reports 15 30166609
2006 Principles of protein-DNA recognition revealed in the structural analysis of Ndt80-MSE DNA complexes. Structure (London, England : 1993) 15 16531239
2019 LUCAT1 contributes to MYRF-dependent smooth muscle cell apoptosis and may facilitate aneurysm formation via the sequestration of miR-199a-5p. Cell biology international 13 31769911
2018 Degradation of the endoplasmic reticulum-anchored transcription factor MyRF by the ubiquitin ligase SCFFbxw7 in a manner dependent on the kinase GSK-3. The Journal of biological chemistry 13 29472293
2016 Unh1, an Ustilago maydis Ndt80-like protein, controls completion of tumor maturation, teliospore development, and meiosis. Fungal genetics and biology : FG & B 13 27397931
2015 Extreme Diversity in the Regulation of Ndt80-Like Transcription Factors in Fungi. G3 (Bethesda, Md.) 13 26497142
2021 Nanophthalmos-Associated MYRF Gene Mutation Causes Ciliary Zonule Defects in Mice. Investigative ophthalmology & visual science 12 33646289
2021 The LRR-TM protein PAN-1 interacts with MYRF to promote its nuclear translocation in synaptic remodeling. eLife 11 33950834
2024 Essential function of transmembrane transcription factor MYRF in promoting transcription of miRNA lin-4 during C. elegans development. eLife 10 38963411
2021 The transcription factor Ndt80 is a repressor of Candida parapsilosis virulence attributes. Virulence 10 33538224
2002 Crystallographic studies of a novel DNA-binding domain from the yeast transcriptional activator Ndt80. Acta crystallographica. Section D, Biological crystallography 10 12454476
2022 Case report: Mild encephalitis with a reversible splenial lesion associated with SARS-CoV-2 infection in a patient with MYRF variant. Frontiers in pediatrics 9 35990002
2008 Investigation of transcription factor Ndt80 affinity differences for wild type and mutant DNA: a molecular dynamics study. Proteins 9 18433057
2004 Purification and characterization of the DNA binding domain of Saccharomyces cerevisiae meiosis-specific transcription factor Ndt80. Protein expression and purification 9 14680970
2024 MYRF: A unique transmembrane transcription factor- from proteolytic self-processing to its multifaceted roles in animal development. BioEssays : news and reviews in molecular, cellular and developmental biology 8 38488284
2023 Two sisters with cardiac-urogenital syndrome secondary to pathogenic splicing variant in the MYRF gene with unaffected parents: A case of gonadal mosaicism? Molecular genetics & genomic medicine 8 36695166
2022 The NDT80-like transcription factor CmNdt80a affects the conidial formation and germination, mycoparasitism, and cell wall integrity of Coniothyrium minitans. Journal of applied microbiology 8 35429104
2022 Truncation mutations in MYRF underlie primary angle closure glaucoma. Human genetics 8 36129575
2020 Nanophthalmos patient with a THR518MET mutation in MYRF, a case report. BMC ophthalmology 8 33004036
2016 Ndt80 activates the meiotic ORC1 transcript isoform and SMA2 via a bi-directional middle sporulation element in Saccharomyces cerevisiae. RNA biology 8 27362276
2022 MYRF: A New Regulator of Cardiac and Early Gonadal Development-Insights from Single Cell RNA Sequencing Analysis. Journal of clinical medicine 7 36013096
2016 Suppressor of fusion, a Fusarium oxysporum homolog of Ndt80, is required for nutrient-dependent regulation of anastomosis. Fungal genetics and biology : FG & B 7 27531696
2003 Lateral elements inside synaptonemal complex-like polycomplexes in ndt80 mutants of yeast bind DNA. Genetics 7 12618393
2021 Crystal structure of the MyRF ICA domain with its upstream β-helical stalk reveals the molecular mechanisms underlying its trimerization and self-cleavage. International journal of biological sciences 6 34345217
2023 CRISPR-based knockout and base editing confirm the role of MYRF in heart development and congenital heart disease. Disease models & mechanisms 5 37584388
2025 Myelin regulatory factor (MYRF) is a critical early regulator of retinal pigment epithelial development. PLoS genetics 4 40233131
2021 Evaluation of MYRF as a candidate gene for primary angle closure glaucoma. Molecular vision 4 35136345
2026 MYRF controls mesothelium specification, signaling, and plasticity in lung development. Developmental cell 3 41558485
2025 MYRF Variants in Patients With 46,XY Differences/Disorders of Sex Development and Literature Review. American journal of medical genetics. Part A 2 39868768
2025 FBXW7 regulates MYRF levels to control myelin capacity and homeostasis in the adult central nervous system. Nature communications 2 40841354
2024 MYRF mutation leads to a single manifestation of sexual development and mimics partial androgen insensitivity syndrome: a case report and literature review. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 2 38547923
2023 [Analysis of MYRF gene variant in a fetus with Cardiac-urogenital syndrome]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 2 37102290
2026 Dual Inhibition of MYRF Cleavage by Its JM Region and PAN-1 CCT Gates Developmental Timing in C. elegans. bioRxiv : the preprint server for biology 1 41542402
2025 MYRF is Essential in Mesothelial Cells to Promote Lung Development and Maturation. bioRxiv : the preprint server for biology 1 39990361
2025 Splicing variants in MYRF cause partial loss of function in the retinal pigment epithelium. bioRxiv : the preprint server for biology 1 40313921
2025 MYRF gene mutation leading to coronary artery anomaly combined with 46,XY sex development disorder, a case report and literature review. BMC pediatrics 1 40819034
2025 Identification of a novel variant in MYRF gene in a patient with 46, XX disorders of sex development. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 1 40931513
2025 Non-apoptotic death of the C. elegans linker cell is primed by MYRF-1 activation of pqn-41/polyQ. bioRxiv : the preprint server for biology 1 41427293
2024 Nanophthalmos-Associated MYRF gene mutation facilitates intraocular inflammation in mice. International immunopharmacology 1 38901241
2024 FBXW7 regulates MYRF levels to control myelin capacity and homeostasis in the adult CNS. bioRxiv : the preprint server for biology 1 39464137
2023 DUSP15 expression is reduced in the hippocampus of Myrf knock-out mice but attention and object recognition memory remain intact. PloS one 1 36730342
2026 MYRF drives heterochronic miRNAs and LIN-42, and amplifies oscillatory programs for stage transitions. bioRxiv : the preprint server for biology 0 41659655
2026 Splicing variants in MYRF cause partial loss of function in the retinal pigment epithelium leading to nanophthalmos. JCI insight 0 41746734
2026 MYRF restrains mesothelial plasticity to protect the lung. Developmental cell 0 41819068
2026 Impact of Candida albicans NDT80 and UME6 on biofilm formation and fluconazole susceptibility. mSphere 0 41891724
2026 Ndt80 Orchestrates Copper Stress Responses and Mitochondrial Homeostasis in Candida albicans. Journal of fungi (Basel, Switzerland) 0 42042388
2026 Large transgene arrays cause aberrant transcription and synthetic molting defects with myrf-1 mutation. bioRxiv : the preprint server for biology 0 42146662
2026 A Specific tRNA Half, 3'tiRNA-GlyGCC, Regulates Hypoxic Pulmonary Artery Smooth Muscle Cell Proliferation via Myrf-Mediated Endoplasmic Reticulum Stress. Cell proliferation 0 42215285
2025 Anomalous Left Coronary Artery from the Pulmonary Artery in Three Patients with MYRF-Associated Cardiac-Urogenital Syndrome. Pediatric cardiology 0 39779519
2025 Two Cases of MYRF-Related Differences of Sex Development: A Wide Phenotypic Spectrum. JCEM case reports 0 41347118
2024 Myelin regulatory factor ( Myrf ) is a critical early regulator of retinal pigment epithelial development. bioRxiv : the preprint server for biology 0 38746430

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