# Mef2

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Protein family

Dimeric structure of the MADS (red) and MEF2 (green) domains of the human [MEF2B](/source/MEF2B) transcription factor complexed with DNA (orange) based on the [PDB](/source/Protein_Data_Bank): [1N6J](https://www.rcsb.org/structure/1N6J)​ [crystallographic](/source/X-ray_crystallography) coordinates.

The domain organization and sequence comparison of Mef2 proteins from representative species.[1]  The amino acid numbering shown is of the human [MEF2A](/source/MEF2A) sequence and the per cent sequence identities are all relative to hMEF2A. The three domain, MADS (red), MEF2 (green), and transactivation domains (TAD; cyan) are each highlighted in a different color.

In the field of [molecular biology](/source/Molecular_biology), **myocyte enhancer factor-2** (**Mef2**) [proteins](/source/Protein) are a family of [transcription factors](/source/Transcription_factor) which through control of [gene expression](/source/Gene_expression) are important regulators of [cellular differentiation](/source/Cellular_differentiation) and consequently play a critical role in embryonic [development](/source/Developmental_biology).[1] In adult organisms, Mef2 proteins mediate the [stress](/source/Stress_(biological)) response in some tissues.[1] Mef2 proteins contain both [MADS-box](/source/MADS-box) and Mef2 [DNA-binding domains](/source/DNA-binding_domain).

## Discovery

Mef2 was originally identified as a transcription factor complex through [promoter](/source/Promoter_(biology)) analysis of the muscle [creatine kinase](/source/Creatine_kinase) (mck) [gene](/source/Gene) to identify nuclear factors interacting with the mck [enhancer](/source/Enhancer_(genetics)) region during muscle differentiation.[2] Three human mRNA [coding sequences](/source/Coding_sequence) designated RSRF (Related to [Serum Response Factor](/source/Serum_response_factor)) were cloned and shown to dimerize, bind a consensus sequence similar to the one present in the MCK enhancer region, and drive transcription.[3] RSRFs were subsequently demonstrated to encode human genes now named Mef2A, Mef2B and Mef2D.

## Species distribution

The Mef2 gene is widely expressed in all branches of [eukaryotes](/source/Eukaryote) from [yeast](/source/Yeast) to humans. While Drosophila has a single Mef2 gene, [vertebrates](/source/Vertebrate) have at least four versions of the Mef2 gene (human versions are denoted as [MEF2A](/source/Myocyte-specific_enhancer_factor_2A), [MEF2B](/source/MEF2B), [MEF2C](/source/MEF2C), and [MEF2D](/source/MEF2D)), all [expressed](/source/Gene_expression) in distinct but overlapping patterns during embryogenesis through adulthood.[4]

## Sequence and structure

All of the mammalian Mef2 genes share approximately 50% overall amino acid identity and about 95% similarity throughout the highly conserved [N-terminal](/source/N-terminal) MADS-box and Mef2 domains, however their sequences diverge in their [C-terminal](/source/C-terminal) transactivation domain (see figure to the right).[5]

The MADS-box serves as the minimal DNA-binding domain, however an adjacent 29-amino acid extension called the Mef2 domain is required for high affinity DNA-binding and dimerization. Through an interaction with the MADS-box, Mef2 transcription factors have the ability to homo- and heterodimerize,[6] and a classic nuclear localization sequence ([NLS](/source/Nuclear_localization_signal)) in the C-terminus of Mef2A, -C, and – D ensures nuclear localization of the protein.[7] D-Mef2 and human MEF2B lack this conserved NLS but are still found in the nucleus.[8]

## Function

### Development

In *Drosophila*, Mef2 regulates muscle development.[9] Mammalian Mef2 can cooperate with [bHLH](/source/Basic_helix-loop-helix) transcription factors to turn non-muscle cells in culture into muscle.[10] bHLH factors can activate Mef2c expression, which then acts to maintain its own expression.[11]

Loss of Mef2c in [neural crest](/source/Neural_crest) cells results in [craniofacial](/source/Craniofacial) defects in the developing embryo and neonatal death caused by blocking of the upper airway passages.[12][13] Mef2c upregulates the expression of the [homeodomain](/source/Homeodomain) transcription factors [DLX5](/source/DLX5) and [DLX6](/source/DLX6), two transcription factors that are necessary for craniofacial development.[12][13]

### Stress response

In adult tissues, Mef2 proteins regulate the stress-response during [cardiac hypertrophy](/source/Ventricular_hypertrophy)[14] and tissue remodeling in cardiac and skeletal muscle.[15]

### Cardiovascular system

Mef2 is a critical regulator in heart development and cardiac gene expression.[16] In vertebrates, there are four genes in the Mef2 transcription factor family: Mef2a, Mef2b, Mef2c, and Mef2d. Each is expressed at specific times during development. Mef2c, the first gene to be expressed in the heart, is necessary for the development of the anterior (secondary) heart field (AHF), which helps to form components of the cardiac outflow tract and most of the right ventricle.[17][18] In addition, Mef2 genes are indicated in activating gene expression to aid in sprouting angiogenesis, the formation of new blood vessels from existing vessels.[19]

## Knockout studies

In mice, knockout studies of Mef2c have demonstrated that crucial role that it plays in heart development. Mice without the Mef2c die during embryonic day 9.5–10 with major heart defects, including improper looping, outflow tract abnormalities, and complete lack of the right ventricle.[16] This indicates improper differentiation of the anterior heart field. When Mef2c is knocked out specifically in the AHF, the mice die at birth with a range of outflow tract defects and severe cyanosis. Thus, Mef2 is necessary for many aspects of heart development, specifically by regulating the anterior heart field.[20]

## Additional Information

MEF2, Myocyte Enhancer Factor 2, is a transcription factor with four specific numbers such as MEF2A, B, C, and D. Each MEF2 gene is located on a specific chromosome. MEF2 is known to be involved in the development and the looping of the heart (Chen) MEF2 is necessary for myocyte differentiation and gene activation (Black). Both roles contribute to the heart structure, and if there is a disruption with MEF2 in embryonic development, it can lead to two phenotypic problems (Karamboulas). The Type-I phenotype can cause severe malformations to the heart and the type-II phenotype, while it looks normal, has a thin-walled myocardium which can cause cardiac insufficiency. Another problem that can arise is from the knockout gene MEF2C. MEF2C is known to be directly related to congenital heart disease when associated with Tdgf1 (teratocarcinoma-derived growth factor 1). If MEF2C improperly regulates Tdgf1, developmental defects arise, especially within the embryonic development of the heart. (Chen). The way that MEF2C interacts with the protein Tdgf1 is through the 〖Ca〗^(2+) signaling pathway, which is required to regulate different mechanisms. MicroRNA's, non-small coding RNAs, also play a specific role in regulating MEF2C. The expression of congenital heart disease is upregulated due to the downregulation of the microRNA miR-29C (Chen). A few other known diseases associated with the MEF2 family are liver fibrosis, cancers, and neurodegenerative diseases (Chen).

## References

1. ^ [***a***](#cite_ref-pmid17959722_1-0) [***b***](#cite_ref-pmid17959722_1-1) [***c***](#cite_ref-pmid17959722_1-2) Potthoff MJ, Olson EN (December 2007). "MEF2: a central regulator of diverse developmental programs". *Development*. **134** (23): 4131–40. [doi](/source/Doi_(identifier)):[10.1242/dev.008367](https://doi.org/10.1242%2Fdev.008367). [PMID](/source/PMID_(identifier)) [17959722](https://pubmed.ncbi.nlm.nih.gov/17959722). [S2CID](/source/S2CID_(identifier)) [27125540](https://api.semanticscholar.org/CorpusID:27125540).

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1. ^ [***a***](#cite_ref-pmid17420000_12-0) [***b***](#cite_ref-pmid17420000_12-1) Verzi MP, Agarwal P, Brown C, McCulley DJ, Schwarz JJ, Black BL (April 2007). ["The transcription factor MEF2C is required for craniofacial development"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1920108). *Dev. Cell*. **12** (4): 645–52. [doi](/source/Doi_(identifier)):[10.1016/j.devcel.2007.03.007](https://doi.org/10.1016%2Fj.devcel.2007.03.007). [PMC](/source/PMC_(identifier)) [1920108](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1920108). [PMID](/source/PMID_(identifier)) [17420000](https://pubmed.ncbi.nlm.nih.gov/17420000).

1. ^ [***a***](#cite_ref-pmid17574232_13-0) [***b***](#cite_ref-pmid17574232_13-1) Miller CT, Swartz ME, Khuu PA, Walker MB, Eberhart JK, Kimmel CB (August 2007). ["mef2ca is required in cranial neural crest to effect Endothelin1 signaling in zebrafish"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2148033). *Dev. Biol*. **308** (1): 144–57. [doi](/source/Doi_(identifier)):[10.1016/j.ydbio.2007.05.018](https://doi.org/10.1016%2Fj.ydbio.2007.05.018). [PMC](/source/PMC_(identifier)) [2148033](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2148033). [PMID](/source/PMID_(identifier)) [17574232](https://pubmed.ncbi.nlm.nih.gov/17574232).

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Black, Brian L., and Richard M. Cripps. “Myocyte Enhancer Factor 2 Transcription Factors in Heart Development and Disease.” Heart Development and Regeneration, 2010, pp. 673–699., doi:10.1016/b978-0-12-381332-9.00030-x.

Chen, Xiao, et al. “MEF2 Signaling and Human Diseases.” Oncotarget, vol. 8, no. 67, 2017, pp. 112152–112165., doi:10.18632/oncotarget.22899.

Karamboulas, C., et al. “Disruption of MEF2 Activity in Cardiomyoblasts Inhibits Cardiomyogenesis.” Journal of Cell Science, vol. 120, no. 1, 2006, pp. 4315–4318., doi:10.1242/jcs.03369.

## External links

- [OrthoDB](https://www.orthodb.org/?level=&species=&query=729387at2759) Orthology in all Eukaryotes

- [MEF2+protein,+C+elegans](https://meshb.nlm.nih.gov/record/ui?name=MEF2+protein%2C+C+elegans) at the U.S. National Library of Medicine [Medical Subject Headings](/source/Medical_Subject_Headings) (MeSH)

- [Mef2+protein,+Drosophila](https://meshb.nlm.nih.gov/record/ui?name=Mef2+protein%2C+Drosophila) at the U.S. National Library of Medicine [Medical Subject Headings](/source/Medical_Subject_Headings) (MeSH)

- [Mef2+protein,+zebrafish](https://meshb.nlm.nih.gov/record/ui?name=Mef2+protein%2C+zebrafish) at the U.S. National Library of Medicine [Medical Subject Headings](/source/Medical_Subject_Headings) (MeSH)

- [SMP1+protein,+Arabidopsis](https://meshb.nlm.nih.gov/record/ui?name=SMP1+protein%2C+Arabidopsis) at the U.S. National Library of Medicine [Medical Subject Headings](/source/Medical_Subject_Headings) (MeSH)

- [SMP1+protein,+S+cerevisiae](https://meshb.nlm.nih.gov/record/ui?name=SMP1+protein%2C+S+cerevisiae) at the U.S. National Library of Medicine [Medical Subject Headings](/source/Medical_Subject_Headings) (MeSH)

v t e Transcription factors and intracellular receptors (1) Basic domains (1.1) Basic leucine zipper (bZIP) Activating transcription factor AATF 1 2 3 4 5 6 7 AP-1 c-Fos FOSB FOSL1 FOSL2 JDP2 c-Jun JUNB JunD BACH 1 2 BATF BLZF1 C/EBP α β γ δ ε ζ CREB 1 3 L1 CREM DBP DDIT3 GABPA GCN4 HLF MAF B sMaf F G K NFE 2 L1 L2 L3 NFIL3 NRL NRF 1 2 3 XBP1 (1.2) Basic helix–loop–helix (bHLH) Group A AS-C ASCL1 ASCL2 ATOH1 HAND 1 2 MESP2 Myogenic regulatory factors MyoD Myogenin MYF5 MYF6 NeuroD 1 2 Neurogenins 1 2 3 OLIG 1 2 Paraxis TCF15 Scleraxis SLC LYL1 TAL 1 2 Twist Group B FIGLA Myc c-Myc l-Myc n-Myc MXD4 TCF4 Group C bHLH-PAS AhR AHRR ARNT ARNTL ARNTL2 CLOCK HIF 1A EPAS1 3A NPAS 1 2 3 PER 1 2 3 Period SIM 1 2 Group D DEC 1 2 BHLHA9 Pho4 ID 1 2 3 4 Group E HES 1 2 3 4 5 6 7 HEY 1 2 L Group F bHLH-COE EBF1 (1.3) bHLH-ZIP AP-4 MAX MXD1 MXD3 MITF MNT MLX MLXIPL MXI1 Myc SREBP 1 2 USF1 (1.4) NF-1 NFI A B C X SMAD R-SMAD 1 2 3 5 9 I-SMAD 6 7 4) (1.5) RF-X RFX 1 2 3 4 5 6 ANK (1.6) Basic helix-span-helix (bHSH) AP-2 α β γ δ ε (2) Zinc finger DNA-binding domains (2.1) Nuclear receptor (Cys4) subfamily 1 Thyroid hormone α β CAR FXR LXR α β PPAR α β/δ γ PXR RAR α β γ ROR α β γ Rev-ErbA α β VDR subfamily 2 COUP-TF (I II Ear-2 HNF4 α γ PNR RXR α β γ Testicular receptor 2 4 TLX subfamily 3 Steroid hormone Androgen Estrogen α β Glucocorticoid Mineralocorticoid Progesterone Estrogen related α β γ subfamily 4 NUR NGFIB NOR1 NURR1 subfamily 5 LRH-1 SF1 subfamily 6 GCNF subfamily 0 DAX1 SHP (2.2) Other Cys4 GATA 1 2 3 4 5 6 MTA 1 2 3 TRPS1 (2.3) Cys2His2 General transcription factors TFIIA TFIIB TFIID TFIIE 1 2 TFIIF 1 2 TFIIH 1 2 4 2I 3A 3C1 3C2 ATBF1 BCL 6 11A 11B CTCF E4F1 EGR 1 2 3 4 ERV3 GFI1 GLI family 1 2 3 REST S1 S2 YY1 HIC 1 2 HIVEP 1 2 3 IKZF 1 2 3 ILF 2 3 Sp/KLF family KLF 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 17 SP 1 2 4 7 8 MTF1 MYT1 OSR1 PRDM9 SALL 1 2 3 4 TSHZ3 WT1 Zbtb7 7A 7B ZBTB 11 16 17 20 21 32 33 40 zinc finger 3 7 9 10 19 22 24 33B 34 35 41 43 44 51 74 143 146 148 165 202 217 219 238 239 259 267 268 281 300 318 330 346 350 365 366 384 423 451 452 471 593 638 644 649 655 804A (2.4) Cys6 HIVEP1 (2.5) Alternating composition AIRE DIDO1 GRLF1 ING 1 2 4 JARID 1A 1B 1C 1D 2 JMJD1B (2.6) WRKY WRKY (3) Helix-turn-helix domains (3.1) Homeodomain Antennapedia ANTP class protoHOX Hox-like ParaHox Gsx 1 2 Xlox PDX1 Cdx 1 2 4 extended Hox: Evx1 Evx2 MEOX1 MEOX2 Homeobox A1 A2 A3 A4 A5 A7 A9 A10 A11 A13 B1 B2 B3 B4 B5 B6 B7 B8 B9 B13 C4 C5 C6 C8 C9 C10 C11 C12 C13 D1 D3 D4 D8 D9 D10 D11 D12 D13 GBX1 GBX2 MNX1 metaHOX NK-like BARHL1 BARHL2 BARX1 BARX2 BSX DBX 1 2 DLX 1 2 3 4 5 6 EMX 1 2 EN 1 2 HHEX HLX LBX1 LBX2 MSX 1 2 NANOG NKX 2-1 2-2 2-3 2-5 3-1 3-2 HMX1 HMX2 HMX3 6-1 6-2 NOTO TLX1 TLX2 TLX3 VAX1 VAX2 other ARX CRX CUTL1 FHL 1 2 3 HESX1 HOPX LMX 1A 1B NOBOX TALE IRX 1 2 3 4 5 6 MKX MEIS 1 2 PBX 1 2 3 PKNOX 1 2 SIX 1 2 3 4 5 PHF 1 3 6 8 10 16 17 20 21A POU domain PIT-1 BRN-3: A B C Octamer transcription factor: 1 2 3/4 6 7 11 SATB2 ZEB 1 2 (3.2) Paired box PAX 1 2 3 4 5 6 7 8 9 PRRX 1 2 PROP1 PHOX 2A 2B RAX SHOX SHOX2 VSX1 VSX2 Bicoid GSC BICD2 OTX 1 2 PITX 1 2 3 (3.3) Fork head / winged helix E2F 1 2 3 4 5 FOX proteins A1 A2 A3 B1 B2 C1 C2 D1 D2 D3 D4 D4L1 D4L3 D4L4 D4L5 D4L6 E1 E3 F1 F2 G1 H1 I1 I2 I3 J1 J2 J3 K1 K2 L1 L2 M1 N1 N2 N3 N4 O1 O3 O4 O6 P1 P2 P3 P4 Q1 R1 R2 S1 (3.4) Heat shock factors HSF 1 2 4 (3.5) Tryptophan clusters ELF 2 4 5 EHF ELK 1 3 4 ERF ETS 1 2 ERG SPIB ETV 1 4 5 6 FLI1 Interferon regulatory factors 1 2 3 4 5 6 7 8 MYB MYBL2 (3.6) TEA domain transcriptional enhancer factor 1 2 3 4 (4) β-Scaffold factors with minor groove contacts (4.1) Rel homology region NF-κB NFKB1 NFKB2 REL RELA RELB NFAT C1 C2 C3 C4 5 (4.2) STAT STAT 1 2 3 4 5 6 (4.3) p53-like p53 p63 p73 family p53 TP63 p73 TBX 1 2 3 5 19 21 22 TBR1 TBR2 TFT MYRF (4.4) MADS box Mef2 A B C D SRF (4.6) TATA-binding proteins TBP TBPL1 (4.7) High-mobility group BBX HMGB 1 2 3 4 HMGN 1 2 3 4 HNF 1A 1B SOX 1 2 3 4 5 6 8 9 10 11 12 13 14 15 17 18 21 SRY SSRP1 TCF/LEF TCF 1 3 4 LEF1 TOX 1 2 3 4 (4.9) Grainyhead TFCP2 (4.10) Cold-shock domain CSDA YBX1 (4.11) Runt CBF CBFA2T2 CBFA2T3 RUNX1 RUNX2 RUNX3 RUNX1T1 (0) Other transcription factors (0.2) HMGI(Y) HMGA 1 2 HBP1 (0.3) Pocket domain Rb RBL1 RBL2 (0.5) AP-2/EREBP-related factors Apetala 2 EREBP B3 (0.6) Miscellaneous ARID 1A 1B 2 3A 3B 4A CAP IFI 16 35 MLL 2 3 T1 MNDA NFY A B C Rho/Sigma see also transcription factor/coregulator deficiencies

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Adapted from the Wikipedia article [Mef2](https://en.wikipedia.org/wiki/Mef2) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Mef2?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.