Mef2

Mef2 was originally identified as a transcription factor complex through promoter analysis of the muscle creatine kinase (mck) gene to identify nuclear factors interacting with the mck enhancer region during muscle differentiation.{{cite journal |vauthors=Gossett LA, Kelvin DJ, Sternberg EA, Olson EN | title = A new myocyte-specific enhancer-binding factor that recognizes a conserved element associated with multiple muscle-specific genes | journal = Mol. Cell. Biol. | volume = 9 | issue = 11 | pages = 5022–33 | date=1 November 1989| pmid = 2601707 | pmc = 363654 | doi = 10.1128/MCB.9.11.5022 }} Three human mRNA coding sequences designated RSRF (Related to 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.{{cite journal |vauthors=Pollock R, Treisman R | title=Human SRF-related proteins: DNA-binding properties and potential regulatory targets | journal = Genes Dev. | pages = 2327–41 |date = 1991 | pmid = 1748287 | doi=10.1101/gad.5.12a.2327 | volume=5| issue=12a | doi-access=free }} RSRFs were subsequently demonstrated to encode human genes now named Mef2A, Mef2B and Mef2D.

The Mef2 gene is widely expressed in all branches of eukaryotes from yeast to humans. While Drosophila has a single Mef2 gene, vertebrates have at least four versions of the Mef2 gene (human versions are denoted as MEF2A, MEF2B, MEF2C, and MEF2D), all expressed in distinct but overlapping patterns during embryogenesis through adulthood.{{cite journal |vauthors=McKinsey TA, Zhang CL, Olson EN |title=MEF2: a calcium-dependent regulator of cell division, differentiation and death |journal=Trends Biochem. Sci. |volume=27 |issue=1 |pages=40–7 |year=2002 |pmid=11796223 |doi=10.1016/S0968-0004(01)02031-X}}

All of the mammalian Mef2 genes share approximately 50% overall amino acid identity and about 95% similarity throughout the highly conserved N-terminal MADS-box and Mef2 domains, however their sequences diverge in their C-terminal transactivation domain (see figure to the right).{{cite journal |vauthors=Black BL, Olson EN |title=Transcriptional control of muscle development by myocyte enhancer factor-2 (MEF2) proteins |journal=Annu Rev Cell Dev Biol |volume=14 |pages=167–96 |year=1998 |pmid=9891782 |doi=10.1146/annurev.cellbio.14.1.167}}

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,{{cite journal |vauthors=Molkentin JD, Olson EN |title=Combinatorial control of muscle development by basic helix-loop-helix and MADS-box transcription factors |journal=Proc Natl Acad Sci USA |volume=93 |issue=18 |pages=9366–73 |year=1996 |pmid=8790335 |doi=10.1073/pnas.93.18.9366 |pmc=38433|bibcode=1996PNAS...93.9366M |doi-access=free }} and a classic nuclear localization sequence (NLS) in the C-terminus of Mef2A, -C, and – D ensures nuclear localization of the protein.{{cite journal |vauthors=Borghi S, Molinari S, Razzini G, Parise F, Battini R, Ferrari S |title=The nuclear localization domain of the Mef2 family of transcription factors shows member-specific features and mediates the nuclear import of histone deacetylase 4 |journal=J Cell Sci |volume=114 |pages=4477–83 |year=2001 |pmid=11792813 |issue=Pt 24|doi=10.1242/jcs.114.24.4477 }} D-Mef2 and human MEF2B lack this conserved NLS but are still found in the nucleus.{{cite journal |author=Yu YT |title=Distinct domains of myocyte enhancer binding factor-2A determining nuclear localization and cell type-specific transcriptional activity |journal=J Biol Chem |volume=271 |issue=40 |pages=24675–83 |year=1996 |pmid=8798735 | doi = 10.1016/S0021-9258(18)40058-0 |s2cid=25878690|doi-access=free }}

In Drosophila, Mef2 regulates muscle development.{{cite journal |vauthors=Lilly B, Galewsky S, Firulli AB, Schulz RA, Olson EN | title = D-MEF2: a MADS box transcription factor expressed in differentiating mesoderm and muscle cell lineages during Drosophila embryogenesis | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 91 | issue = 12 | pages = 5662–6 |date=June 1994 | pmid = 8202544 | pmc = 44056 | doi = 10.1073/pnas.91.12.5662 | bibcode = 1994PNAS...91.5662L | doi-access = free }} Mammalian Mef2 can cooperate with bHLH transcription factors to turn non-muscle cells in culture into muscle.{{cite journal |vauthors=Molkentin JD, Black BL, Martin JF, Olson EN | title = Cooperative activation of muscle gene expression by MEF2 and myogenic bHLH proteins | journal = Cell | volume = 83 | issue = 7 | pages = 1125–36 |date=December 1995 | pmid = 8548800 | doi = 10.1016/0092-8674(95)90139-6 | s2cid = 14140159 | doi-access = free }} bHLH factors can activate Mef2c expression, which then acts to maintain its own expression.{{cite journal |vauthors=Wang DZ, Valdez MR, McAnally J, Richardson J, Olson EN | title = The Mef2c gene is a direct transcriptional target of myogenic bHLH and MEF2 proteins during skeletal muscle development | journal = Development | volume = 128 | issue = 22 | pages = 4623–33 |date=November 2001 | doi = 10.1242/dev.128.22.4623 | pmid = 11714687 | url = http://dev.biologists.org/cgi/pmidlookup?view=long&pmid=11714687 | url-access = subscription }}

Loss of Mef2c in neural crest cells results in craniofacial defects in the developing embryo and neonatal death caused by blocking of the upper airway passages.{{cite journal |vauthors=Verzi MP, Agarwal P, Brown C, McCulley DJ, Schwarz JJ, Black BL | title = The transcription factor MEF2C is required for craniofacial development | journal = Dev. Cell | volume = 12 | issue = 4 | pages = 645–52 |date=April 2007 | pmid = 17420000 | pmc = 1920108 | doi = 10.1016/j.devcel.2007.03.007 }}{{cite journal |vauthors=Miller CT, Swartz ME, Khuu PA, Walker MB, Eberhart JK, Kimmel CB | title = mef2ca is required in cranial neural crest to effect Endothelin1 signaling in zebrafish | journal = Dev. Biol. | volume = 308 | issue = 1 | pages = 144–57 |date=August 2007 | pmid = 17574232 | doi = 10.1016/j.ydbio.2007.05.018 | pmc = 2148033 }} Mef2c upregulates the expression of the homeodomain transcription factors DLX5 and DLX6, two transcription factors that are necessary for craniofacial development.

In adult tissues, Mef2 proteins regulate the stress-response during cardiac hypertrophy{{cite journal |vauthors=Zhang CL, McKinsey TA, Chang S, Antos CL, Hill JA, Olson EN | title = Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy | journal = Cell | volume = 110 | issue = 4 | pages = 479–88 |date=August 2002 | pmid = 12202037 | pmc = 4459650 | doi = 10.1016/S0092-8674(02)00861-9 }} and tissue remodeling in cardiac and skeletal muscle.{{cite journal |vauthors=Potthoff MJ, Wu H, Arnold MA, Shelton JM, Backs J, McAnally J, Richardson JA, Bassel-Duby R, Olson EN | title = Histone deacetylase degradation and MEF2 activation promote the formation of slow-twitch myofibers | journal = J. Clin. Invest. | volume = 117 | issue = 9 | pages = 2459–67 |date=September 2007 | pmid = 17786239 | pmc = 1957540 | doi = 10.1172/JCI31960 }}

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Mef2 is a critical regulator in heart development and cardiac gene expression.{{cite journal | vauthors = Anderson CM, Hu J, Thomas R, Gainous B, Celona B, Sinha T, Dickel DE, Heidt AB, Xu SM, Bruneau BG, Pollard KS, Pennacchio LA, Black BL | year = 2017 | title = Cooperative activation of cardiac transcription through myocardin bridging of paired MEF2 sites | journal = Development | volume = 144 | issue = 7| pages = 1234–1241 | doi = 10.1242/dev.138487 | pmid = 28351867 | pmc = 5399617 }} 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.. Barnes RM, Harris IS, Jaehnig EJ, Sauls K, Sinha T, Rojas A, Schachterle W, McCulley DJ, Norris RA, Black BL. (January 2016). "Mef2c regulates outflow tract alignment and transcriptional control of Tdgf1." Development. 143: 774-779. oi:10.1242/dev.126383{{cite journal | vauthors = Verzi MP, McCulley DJ, De Val S, Dodou E, Black BL | year = 2005 | title = The right ventricle, outflow tract, and ventricular septum comprise a restricted expression domain within the secondary/anterior heart field | journal = Developmental Biology | volume = 287 | issue = 1| pages = 134–145 | doi=10.1016/j.ydbio.2005.08.041| pmid = 16188249 | doi-access = free }} In addition, Mef2 genes are indicated in activating gene expression to aid in sprouting angiogenesis, the formation of new blood vessels from existing vessels.{{cite journal | vauthors = Sacilotto N, Chouliaras KM, Nikitenko LL, Lu YW, Fritzsche M, Wallace MD, Nornes S, Garcia-Moreno F, Payne S, Bridges E, Liu K, Biggs D, Ratnayaka I, Herbert SP, Molnar Z, Harris AL, Davies B, Bond GL, Bou-Gharios G, Shwarz JJ, De Val S | year = 2016 | title = MEF2 transcription factors are key regulators of sprouting angiogenesis | journal = Genes Dev | volume = 30 | issue = 20| pages = 2297–2309 | doi = 10.1101/gad.290619.116 | pmid = 27898394 | pmc = 5110996 }}

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. 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.Barnes RM, Harris IS, Jaehnig EJ, Sauls K, Sinha T, Rojas A, Schachterle W, McCulley DJ, Norris RA, Black BL. (January 2016). "Mef2c regulates outflow tract alignment and transcriptional control of Tdgf1." Development. 143: 774-779. oi:10.1242/dev.126383

==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).

{{Reflist|30em}}

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.

• [https://www.orthodb.org/?level=&species=&query=729387at2759 OrthoDB] Orthology in all Eukaryotes
• {{MeshName|MEF2+protein,+C+elegans}}
• {{MeshName|Mef2+protein,+Drosophila}}
• {{MeshName|Mef2+protein,+zebrafish}}
• {{MeshName|SMP1+protein,+Arabidopsis}}
• {{MeshName|SMP1+protein,+S+cerevisiae}}

{{Transcription factors|g4}}

Category:Drosophila melanogaster genes

Category:Transcription factors