Mef2 (D-mef2) encodes the single Drosophila member of the MEF2 family of MADS-box transcription factors. It is expressed throughout the mesoderm after gastrulation as a Twist target and is then maintained in somatic, visceral and cardiac muscle lineages, with its cardiac expression driven by a Tinman-dependent enhancer. D-MEF2 dimerizes through its MADS/MEF2 domains and binds A/T-rich MEF2 sites in enhancers of muscle structural genes, fusion genes (e.g. singles bar) and microRNA genes (miR-92b, which feeds back to limit Mef2 levels), activating transcription alone or with cofactors such as CF2. It is not needed for myoblast specification but is required for differentiation of somatic, visceral and cardiac muscle, for myoblast fusion in embryos and pupae, and for adult flight muscle formation, with different targets responding to different Mef2 activity levels. Outside muscle, Mef2 is required in clock neurons for circadian behavioral rhythms and in the adult fat body, where it promotes lipogenic and glycogenic gene expression and, upon infection, partners with TBP to induce antimicrobial peptides.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro (MEF2-like N-terminal/MADS) mapping to Pol II regulatory region sequence-specific DNA binding. Reason: D-MEF2 binds A/T-rich MEF2 sites (CTA(A/T)4TAG) in muscle gene enhancers; MADS-box point mutants lose DNA binding. Supporting Evidence: PMID:7839146 These factors bind an adenine-thymidine-rich DNA sequence associated with muscle-specific genes PMID:12366381 Mutation of these invariant residues results in the inability of mutant D-MEF2 proteins to bind DNA in vitro, muscle defects within the embryo, and adverse effects on the structure of indirect flight muscles within the adult |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of Pol II cis-regulatory region sequence-specific DNA binding for the MEF2 clade. Reason: Directly demonstrated for D-MEF2 on the sing, Act57B and miR-92b enhancers. Supporting Evidence: PMID:25797154 Actin57B exhibited strong binding to MEF2 PMID:22899845 Mef2 directly activates miR-92b through three conserved Mef2-binding sites in the cis-regulatory region of miR-92b |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: Pol II-specific DNA-binding transcription factor activity inferred for the MEF2 clade. Reason: Core molecular function of D-MEF2: sequence-specific activator of muscle structural and fusion genes. Supporting Evidence: PMID:25797154 This enhancer was active during myoblast fusion, and mutation of two MEF2 sites significantly decreased enhancer activity PMID:18160709 MEF2 and CF2 synergistically activate the enhancers of a number of muscle-specific genes |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA machine-learning inference of Pol II DNA-binding TF activity. Reason: Correct; matches experimental evidence. Supporting Evidence: PMID:25797154 This enhancer was active during myoblast fusion, and mutation of two MEF2 sites significantly decreased enhancer activity PMID:18160709 MEF2 and CF2 synergistically activate the enhancers of a number of muscle-specific genes |
| GO:0000987 cis-regulatory region sequence-specific DNA binding | IDA PMID:25797154 Identification of singles bar as a direct transcriptional ta... | ACCEPT | Summary: EMSA with in vitro translated MEF2 on MEF2 sites of the sing myoblast enhancer and the Act57B control site. Reason: Direct DNA-binding evidence; the sites are required for enhancer activity in vivo. Supporting Evidence: PMID:25797154 Actin57B exhibited strong binding to MEF2 PMID:25797154 This enhancer was active during myoblast fusion, and mutation of two MEF2 sites significantly decreased enhancer activity |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IDA PMID:18160709 Myocyte enhancer factor 2 and chorion factor 2 collaborate i... | ACCEPT | Summary: MEF2 activates Actin57B and other muscle gene enhancers, alone and synergistically with CF2. Reason: Transcriptional activation of Pol II muscle genes by a sequence-specific factor. Supporting Evidence: PMID:18160709 although both MEF2 and CF2 can individually activate actin gene expression PMID:18160709 MEF2 and CF2 synergistically activate the enhancers of a number of muscle-specific genes |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IMP PMID:25747460 A cis-regulatory mutation in troponin-I of Drosophila reveal... | ACCEPT | Summary: Mef2 requirement for expression of the troponin-I (wupA) gene via its cis-regulatory region, from the fliH flightless mutant study. Reason: The cached abstract does not mention Mef2 (full text not cached), but Mef2 activator function on muscle structural genes is well established; deferring to the curator. Supporting Evidence: PMID:18160709 MEF2 and CF2 synergistically activate the enhancers of a number of muscle-specific genes |
| GO:0003677 DNA binding | IDA PMID:12366381 Mutations within the conserved MADS box of the D-MEF2 muscle... | ACCEPT | Summary: Wild-type D-MEF2 binds DNA in vitro whereas MADS-box point mutants do not. Reason: Direct DNA-binding evidence; more specific Pol II cis-regulatory terms are also annotated. Supporting Evidence: PMID:12366381 Mutation of these invariant residues results in the inability of mutant D-MEF2 proteins to bind DNA in vitro, muscle defects within the embryo, and adverse effects on the structure of indirect flight muscles within the adult |
| GO:0003677 DNA binding | IEA GO_REF:0000120 | ACCEPT | Summary: DNA binding from MADS-box InterPro/ARBA mapping. Reason: Correct, general. Supporting Evidence: PMID:12366381 Mutation of these invariant residues results in the inability of mutant D-MEF2 proteins to bind DNA in vitro, muscle defects within the embryo, and adverse effects on the structure of indirect flight muscles within the adult |
| GO:0005515 protein binding | IPI PMID:24075010 MEF2 is an in vivo immune-metabolic switch. | MODIFY | Summary: Endogenous MEF2 co-immunoprecipitates TATA-binding protein (TBP) from infected flies, and a MEF2-TBP complex binds MEF2-TATA sequences of antimicrobial peptide promoters. Reason: Generic protein binding is uninformative; the interaction partner is TBP, so TBP-class protein binding captures the evidence. Proposed replacements: TBP-class protein binding Supporting Evidence: PMID:24075010 MEF2 now associates with the TATA binding protein to bind a distinct TATA box sequence and promote antimicrobial peptide expression |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Nuclear localization inferred for MEF2 family. Reason: Expected for a DNA-binding TF; experimentally observed. Supporting Evidence: PMID:7729689 Later in embryogenesis, its expression is maintained in precursors and differentiated cells of the somatic and visceral musculature, as well as the heart |
| GO:0005634 nucleus | IDA PMID:12397110 The Hox gene abdominal-A specifies heart cell fate in the Dr... | ACCEPT | Summary: D-MEF2 nuclear immunostaining in dorsal vessel cells (used as a marker in the abd-A heart study). Reason: Nuclear localization of D-MEF2 is well established; abstract-only cache, deferring to the curator. Supporting Evidence: PMID:12397110 Mutation of abd-A resulted in a loss of heart-specific markers |
| GO:0005634 nucleus | IDA PMID:7729689 Drosophila MEF2, a transcription factor that is essential fo... | ACCEPT | Summary: Antibody staining shows D-MEF2 protein in mesodermal and muscle nuclei. Reason: Direct observation. Supporting Evidence: PMID:7729689 We show herein that the Drosophila MEF2 protein is expressed throughout the mesoderm following gastrulation |
| GO:0005634 nucleus | IDA PMID:7839146 Requirement of MADS domain transcription factor D-MEF2 for m... | ACCEPT | Summary: D-MEF2 protein localized to nuclei of muscle lineages (Lilly et al. 1995). Reason: Direct observation; abstract-only cache. Supporting Evidence: PMID:7839146 In loss-of-function embryos, somatic, cardiac, and visceral muscle cells did not differentiate, but myoblasts were normally specified and positioned |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic nuclear location. Reason: Correct. Supporting Evidence: PMID:7729689 We show herein that the Drosophila MEF2 protein is expressed throughout the mesoderm following gastrulation |
| GO:0007496 anterior midgut development | IMP PMID:16171793 Organ positioning in Drosophila requires complex tissue-tiss... | KEEP AS NON CORE | Summary: Mef2 mutants used in a study of salivary gland positioning; anterior midgut defects arise from failed visceral mesoderm differentiation. Reason: Midgut morphogenesis defects in mef2 mutants are secondary to loss of visceral muscle differentiation, so this is an indirect consequence of the core muscle differentiation function. Supporting Evidence: PMID:7729689 Midgut morphogenesis is disrupted in the mutant embryos, presumably as a consequence of abnormal development of the visceral mesoderm PMID:16171793 proper differentiation of the visceral and somatic mesoderm is necessary for the glands to attain their final correct position |
| GO:0007498 mesoderm development | IEP PMID:11486054 Patterns of gene expression during Drosophila mesoderm devel... | KEEP AS NON CORE | Summary: Mef2 expression depends on Twist in microarray profiling of twist mutant embryos. Reason: Expression pattern evidence only; Mef2 is a pan-mesodermal Twist target, but its functional role is in later muscle differentiation rather than mesoderm formation per se. Supporting Evidence: PMID:11486054 The results implicate hundreds of genes, many with vertebrate homologs, in stage-specific processes in mesoderm development PMID:7729689 We show herein that the Drosophila MEF2 protein is expressed throughout the mesoderm following gastrulation |
| GO:0007498 mesoderm development | IMP PMID:7729689 Drosophila MEF2, a transcription factor that is essential fo... | KEEP AS NON CORE | Summary: mef2 null embryos lack differentiated muscle in all three mesodermal muscle lineages, though early specification is normal. Reason: Broad and correct, but the specific requirement is in muscle differentiation; more specific muscle terms are core. Supporting Evidence: PMID:7729689 These results indicate that MEF2 is required for later aspects of differentiation of the three major types of musculature, which include body wall muscles, gut musculature, and the heart, in the Drosophila embryo |
| GO:0007507 heart development | TAS PMID:12027431 Control of cardiac development by an evolutionarily conserve... | ACCEPT | Summary: Review of the conserved cardiogenic transcriptional network, in which MEF2 is the differentiation factor downstream of Tinman. Reason: Mef2 is required for cardial cell differentiation (no MHC in mef2 mutant cardial cells) and is a direct Tinman target in the heart. Supporting Evidence: PMID:12027431 revealed an evolutionarily conserved network of signaling pathways and transcription factors that underlies these processes PMID:7729689 In the heart, the cardial cells do not express MHC PMID:9034334 D-mef2 expression in the developing Drosophila heart requires a novel upstream enhancer containing two Tinman binding sites, both of which are essential for enhancer function in cardiac muscle cells |
| GO:0007517 muscle organ development | IMP PMID:12366381 Mutations within the conserved MADS box of the D-MEF2 muscle... | ACCEPT | Summary: MADS-box DNA-binding mutants of D-mef2 are lethal with embryonic muscle defects and abnormal indirect flight muscles. Reason: Core: D-MEF2 is required for differentiation of somatic, visceral and cardiac muscle. Supporting Evidence: PMID:12366381 Mutation of these invariant residues results in the inability of mutant D-MEF2 proteins to bind DNA in vitro, muscle defects within the embryo, and adverse effects on the structure of indirect flight muscles within the adult PMID:7839146 In loss-of-function embryos, somatic, cardiac, and visceral muscle cells did not differentiate, but myoblasts were normally specified and positioned |
| GO:0007520 myoblast fusion | IMP PMID:15955848 A positive feedback loop between Dumbfounded and Rolling peb... | ACCEPT | Summary: D-mef2 mutant embryos are used as myoblast fusion mutants in the Duf/Rols7 study. Reason: D-mef2 mutants fail myoblast fusion; MEF2 directly activates fusion genes such as sing. Supporting Evidence: PMID:15955848 in fusion mutants such as blow, lmd, D-mef2, mbc, sns, and hbs;sns, endogenous Duf or ectopically expressed Duf-Flag becomes clearly visible at the founder/myotube surface PMID:25797154 Our studies define for the first time how MEF2 directly controls fusion at multiple stages of the life cycle |
| GO:0007520 myoblast fusion | IMP PMID:22008792 Differential requirements for Myocyte Enhancer Factor-2 duri... | ACCEPT | Summary: Mef2 RNAi in adult myoblasts blocks myoblast fusion although attraction to founders is normal. Reason: Robust stage-specific evidence; MEF2 controls fusion through direct targets. Supporting Evidence: PMID:22008792 MEF2 is critical at the early stages of adult myoblast fusion: mutant myoblasts are attracted normally to their founder cell targets, but are unable to fuse to form myotubes |
| GO:0007520 myoblast fusion | IMP PMID:25797154 Identification of singles bar as a direct transcriptional ta... | ACCEPT | Summary: MEF2 directly regulates the fusion gene sing via two MEF2 sites, in embryonic and pupal myoblasts. Reason: Mechanistically grounded: transcriptional control of a fusion gene. Supporting Evidence: PMID:25797154 Our studies define for the first time how MEF2 directly controls fusion at multiple stages of the life cycle PMID:25797154 This enhancer was active during myoblast fusion, and mutation of two MEF2 sites significantly decreased enhancer activity |
| GO:0007526 larval somatic muscle development | IMP PMID:22899845 miR-92b regulates Mef2 levels through a negative-feedback ci... | ACCEPT | Summary: Altering Mef2 levels via miR-92b deletion or overexpression disrupts larval somatic muscle development. Reason: Consistent with core muscle differentiation role; dosage-sensitive requirement. Supporting Evidence: PMID:22899845 Deletion of miR-92b caused abnormally high Mef2 expression, leading to muscle defects and lethality |
| GO:0010468 regulation of gene expression | IMP PMID:18198273 mef2 activity levels differentially affect gene expression d... | MODIFY | Summary: Mef2 activity levels determine expression and timing of distinct groups of muscle target genes. Reason: Too general; Mef2 acts as a transcriptional activator of these Pol II muscle genes. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:18198273 groups of mef2-regulated genes respond differently to changes in mef2 activity levels: some require higher levels for their expression than others |
| GO:0010628 positive regulation of gene expression | IDA PMID:22899845 miR-92b regulates Mef2 levels through a negative-feedback ci... | ACCEPT | Summary: Mef2 directly activates the miR-92b gene through three conserved Mef2-binding sites. Reason: Direct activation of a microRNA gene; positive regulation of gene expression is appropriate for non-coding targets. Supporting Evidence: PMID:22899845 Mef2 directly activates miR-92b through three conserved Mef2-binding sites in the cis-regulatory region of miR-92b |
| GO:0019730 antimicrobial humoral response | IMP PMID:24075010 MEF2 is an in vivo immune-metabolic switch. | KEEP AS NON CORE | Summary: Fat-body Mef2 is required for antimicrobial peptide induction after infection; it partners with TBP on MEF2-TATA promoter elements. Reason: Well-supported, but a secondary (fat body) role outside the core myogenic function. Supporting Evidence: PMID:24075010 We show that Mef2 is required in the fat body for anabolic function and the immune response PMID:24075010 MEF2 now associates with the TATA binding protein to bind a distinct TATA box sequence and promote antimicrobial peptide expression |
| GO:0019915 lipid storage | IMP PMID:24075010 MEF2 is an in vivo immune-metabolic switch. | KEEP AS NON CORE | Summary: Fat-body Mef2 promotes expression of lipogenic enzymes and lipid storage. Reason: Indirect via transcriptional control of anabolic enzyme genes; non-core. Supporting Evidence: PMID:24075010 MEF2 is phosphorylated at a conserved site in healthy flies and promotes expression of lipogenic and glycogenic enzymes |
| GO:0030154 cell differentiation | IBA GO_REF:0000033 | ACCEPT | Summary: Cell differentiation inferred for MEF2 clade. Reason: Correct, general; muscle differentiation is the specific context. Supporting Evidence: PMID:7839146 In loss-of-function embryos, somatic, cardiac, and visceral muscle cells did not differentiate, but myoblasts were normally specified and positioned |
| GO:0030154 cell differentiation | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA inference of cell differentiation. Reason: Correct, general. Supporting Evidence: PMID:7839146 In loss-of-function embryos, somatic, cardiac, and visceral muscle cells did not differentiate, but myoblasts were normally specified and positioned |
| GO:0032968 positive regulation of transcription elongation by RNA polymerase II | IDA PMID:18160709 Myocyte enhancer factor 2 and chorion factor 2 collaborate i... | MODIFY | Summary: Positive regulation of transcription elongation attributed to MEF2/CF2 activation of muscle gene enhancers. Reason: Enhancer-reporter activation shows positive regulation of transcription but provides no evidence for an elongation-specific mechanism. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:18160709 MEF2 and CF2 synergistically activate the enhancers of a number of muscle-specific genes |
| GO:0042826 histone deacetylase binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Histone deacetylase binding inferred for the MEF2 clade from vertebrate MEF2-class II HDAC interactions. Reason: The HDAC-binding surface in the MADS/MEF2 domain is conserved, and the IBA node placement is plausible; no direct Drosophila binding evidence is cached. A regulatory interaction rather than a core activity. Supporting Evidence: PMID:22899845 In mammals, transcriptional co-repressors such as the Class II HDACs can repress the activity of Mef2 by directly binding to its DNA-binding domain |
| GO:0045475 locomotor rhythm | IMP PMID:20427646 The transcription factor Mef2 is required for normal circadi... | KEEP AS NON CORE | Summary: Mef2 knockdown or a repressor form of Mef2 in clock neurons abolishes circadian locomotor rhythms. Reason: Solid neuronal role but outside the core muscle differentiation function. Supporting Evidence: PMID:20427646 Knocking down Mef2 expression via RNAi or expressing a repressor form of Mef2 caused flies to lose circadian behavioral rhythms |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: Positive regulation of Pol II transcription inferred for MEF2 clade. Reason: Core process. Supporting Evidence: PMID:18160709 MEF2 and CF2 synergistically activate the enhancers of a number of muscle-specific genes PMID:25797154 This enhancer was active during myoblast fusion, and mutation of two MEF2 sites significantly decreased enhancer activity |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic positive regulation of Pol II transcription. Reason: Correct. Supporting Evidence: PMID:18160709 MEF2 and CF2 synergistically activate the enhancers of a number of muscle-specific genes |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:25747460 A cis-regulatory mutation in troponin-I of Drosophila reveal... | ACCEPT | Summary: Mef2 requirement for troponin-I (wupA) expression. Reason: Abstract-only cache does not mention Mef2; function clearly correct for Mef2, deferring to the curator. Supporting Evidence: PMID:18160709 MEF2 and CF2 synergistically activate the enhancers of a number of muscle-specific genes |
| GO:0046983 protein dimerization activity | IEA GO_REF:0000002 | ACCEPT | Summary: Protein dimerization activity from MADS-box InterPro mapping. Reason: MADS/MEF2 domains mediate dimerization required for DNA binding. Supporting Evidence: PMID:12366381 These motifs are required for DNA binding and dimerization properties |
| GO:0052576 carbohydrate storage | IMP PMID:24075010 MEF2 is an in vivo immune-metabolic switch. | KEEP AS NON CORE | Summary: Fat-body Mef2 promotes glycogenic enzyme expression and carbohydrate (glycogen) storage. Reason: Indirect via transcriptional control; non-core. Supporting Evidence: PMID:24075010 MEF2 is phosphorylated at a conserved site in healthy flies and promotes expression of lipogenic and glycogenic enzymes |
| GO:0055001 muscle cell development | IMP PMID:16325168 Transcription of Myocyte enhancer factor-2 in adult Drosophi... | ACCEPT | Summary: Ecdysone-induced Mef2 up-regulation triggers adult muscle differentiation; forced early Mef2 expression causes premature differentiation. Reason: Consistent with core role as the muscle differentiation regulator. Supporting Evidence: PMID:16325168 Since forced early expression of Mef2 in adult myoblasts leads to premature muscle differentiation |
| GO:0160108 animal gross anatomical part developmental process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA inference of a very general anatomical developmental process. Reason: Not wrong but uninformative; muscle and heart development terms capture the biology. Supporting Evidence: PMID:7839146 In loss-of-function embryos, somatic, cardiac, and visceral muscle cells did not differentiate, but myoblasts were normally specified and positioned |
| GO:0055007 cardiac muscle cell differentiation | IMP PMID:7729689 Drosophila MEF2, a transcription factor that is essential fo... | NEW | Summary: In mef2 null embryos cardial cells are specified but fail to differentiate (no myosin heavy chain expression); D-mef2 cardiac expression is directly activated by Tinman. Reason: D-MEF2 is the transcriptional activator of cardiac muscle structural genes in cardioblasts; the specific cardiac differentiation requirement is not captured in GOA (only general heart development TAS). The term is the module annoton process for MEF2. Supporting Evidence: PMID:7729689 In the heart, the cardial cells do not express MHC PMID:7839146 In loss-of-function embryos, somatic, cardiac, and visceral muscle cells did not differentiate, but myoblasts were normally specified and positioned PMID:9034334 D-mef2 expression in the developing Drosophila heart requires a novel upstream enhancer containing two Tinman binding sites, both of which are essential for enhancer function in cardiac muscle cells |
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Download this section (compressed HTML)Q: How does phosphorylation state of MEF2 switch its partner choice (TBP versus muscle cofactors) and target selection between fat body anabolic genes and antimicrobial peptide genes?
Q: Which Mef2 targets in clock neurons (e.g. Fas2) mediate its role in circadian rhythms, and are these direct?
Experiment: Cardioblast-specific Mef2 depletion after specification, combined with CUT&RUN for Mef2 in the dorsal vessel, to define direct cardiac differentiation targets distinct from somatic muscle targets.
Myocyte enhancer factor 2 (Mef2) encodes a protein that belongs to the MADS-box family of transcription factors and is required for muscle development. It directly activates a large number of muscle protein genes. It also regulates gene expression in other tissues, including the fat body and neural tissue.
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