Alternative titles; symbols
HGNC Approved Gene Symbol: MEF2D
Cytogenetic location: 1q22 Genomic coordinates (GRCh38) : 1:156,463,727-156,500,775 (from NCBI)
For background information on the MEF2 family of regulatory proteins, see MEF2A (600660).
Breitbart et al. (1993) obtained MEF2D cDNAs from an adult cardiac ventricle expression library screened at low stringency with a human MEF2B probe. One of the cDNAs encoded a 521-amino acid protein with highly conserved MADS and MEF2 domains. Breitbart et al. (1993) found that MEF2D occurs as several alternatively spliced transcripts, one of which resembles the Xenopus SRF-related factor SL-1. Unlike the other MEF2 family members, MEF2D is present in undifferentiated myoblasts and may participate in the earliest stages of commitment.
Ikeshima et al. (1995) demonstrated strong expression of MEF2D in the cerebellum and cerebrum of developing mouse brains and also in central nervous system neurons of adult mice, suggesting that it may be involved in the differentiation of neurogenic as well as myogenic cells.
Breitbart et al. (1993) found that recombinantly expressed MEF2D protein showed DNA binding to the MEF2 site.
Potthoff et al. (2007) showed that class II histone deacetylases (e.g., HDAC5; 605315) were selectively degraded by the proteasome in mouse slow, oxidative myofibers, enabling Mef2 to activate the slow myofiber gene program. Forced expression of Hdac5 in skeletal muscle or genetic deletion of Mef2c (600662) or Mef2d blocked activity-dependent fast to slow fiber transformation, whereas expression of hyperactive Mef2c promoted the slow fiber phenotype, enhancing endurance and enabling mice to run almost twice the distance of wildtype littermates.
In a neuronal cell line, Yang et al. (2009) found that chaperone-mediated autophagy regulated the activity of myocyte enhancer factor 2D (MEF2D), a transcription factor required for neuronal survival. MEF2D was observed to continuously shuttle to the cytoplasm, interact with the chaperone Hsc70 (600816), and undergo degradation. Inhibition of chaperone-mediated autophagy caused accumulation of inactive MEF2D in the cytoplasm. MEF2D levels were increased in the brains of alpha-synuclein (163890) transgenic mice and patients with Parkinson disease. Wildtype alpha-synuclein and a Parkinson disease-associated mutant (A53T; 163890.0001) disrupted the MEF2D-Hsc70 binding and led to neuronal death. Thus, Yang et al. (2009) concluded that chaperone-mediated autophagy modulates the neuronal survival machinery, and dysregulation of this pathway is associated with Parkinson disease.
Lee et al. (2010) noted that each MEF2 gene has a highly conserved beta exon between exons 6 and 7 that is alternatively spliced. Inclusion of the beta exon produces an MEF2 isoform that is more robust in activating MEF2-responsive promoters. Lee et al. (2010) showed that Mbnl3 (300413) promoted exclusion of the beta exon from Mef2a and Mef2d transcripts in C2C12 mouse muscle cells, which antagonized muscle differentiation. Ultraviolet crosslinking experiments revealed that Mbnl3 selectively bound to Mef2d intron 7 and silenced beta exon splicing during differentiation. Expression of wildtype Mbnl3 led to a significant decrease in Mef2d transcripts containing the beta exon. Both a mouse cell culture model of myotonic dystrophy (see 160900) and skeletal and cardiac muscle from myotonic dystrophy patients showed elevated expression of MBNL3 mRNA, concomitant with significantly reduced levels of MEF2D transcripts containing the beta exon. Lee et al. (2010) concluded that upregulation of MBNL3 can contribute to the pathology of myotonic dystrophy.
Hobson et al. (1995) mapped the MEF2D gene to chromosome 1q12-q23 using somatic cell hybrid panel DNAs containing deletion or derivative chromosomes.
Stumpf (2020) mapped the MEF2D gene to chromosome 1q22 based on an alignment of the MEF2D sequence (GenBank BC054520.1) with the genomic sequence (GRCh38).
Mouse Mef2D was mapped by Martin et al. (1994) to chromosome 3.
Pulipparacharuvil et al. (2008) found strong nuclear expression of Mef2a and Mef2d throughout the striatum in rat brain. In a rat model, repeated cocaine exposure suppressed striatal Mef2 activity in part through cAMP-dependent inhibition of calcineurin (PPP3CA; 114105) activity. Decreased Mef2 activity promoted an increase in dendritic spine density in the nucleus accumbens. However, Mef2-controlled increase in dendritic spine density was associated with reduced behavioral sensitivity to cocaine, suggesting that the correlation between increased spine density and sensitized behavioral responses may be functionally uncoupled processes.
Breitbart, R. E., Liang, C., Smoot, L. B., Laheru, D. A., Mahdavi, V., Nadal-Ginard, B. A fourth human MEF2 transcription factor, hMEF2D, is an early marker of the myogenic lineage. Development 118: 1095-1106, 1993. [PubMed: 8269842] [Full Text: https://doi.org/10.1242/dev.118.4.1095]
Hobson, G. M., Krahe, R., Garcia, E., Siciliano, M. J., Funanage, V. L. Regional chromosomal assignments for four members of the MADS domain transcription enhancer factor 2 (MEF2) gene family to human chromosomes 15q26, 19p12, 5q14, and 1q12-q23. Genomics 29: 704-711, 1995. [PubMed: 8575763] [Full Text: https://doi.org/10.1006/geno.1995.9007]
Ikeshima, H., Imai, S., Shimoda, K., Hata, J., Takano, T. Expression of a MADS box gene, MEF2D, in neurons of the mouse central nervous system: implication of its binary function in myogenic and neurogenic cell lineages. Neurosci. Lett. 200: 117-120, 1995. [PubMed: 8614558] [Full Text: https://doi.org/10.1016/0304-3940(95)12092-i]
Lee, K.-S., Cao, Y., Witwicka, H. E., Tom, S., Tapscott, S. J., Wang, E. H. RNA-binding protein muscleblind-like 3 (MBNL3) disrupts myocyte enhancer factor 2 (Mef2) beta-exon splicing. J. Biol. Chem. 285: 33779-33787, 2010. [PubMed: 20709755] [Full Text: https://doi.org/10.1074/jbc.M110.124255]
Martin, J. F., Miano, J. M., Hustad, C. M., Copeland, N. G., Jenkins, N. A., Olson, E. N. A Mef2 gene that generates a muscle-specific isoform via alternative mRNA splicing. Molec. Cell. Biol. 14: 1647-1656, 1994. [PubMed: 8114702] [Full Text: https://doi.org/10.1128/mcb.14.3.1647-1656.1994]
Potthoff, M. J., Wu, H., Arnold, M. A., Shelton, J. M., Backs, J., McAnally, J., Richardson, J. A., Bassel-Duby, R., Olson, E. N. Histone deacetylase degradation and MEF2 activation promote the formation of slow-twitch myofibers. J. Clin. Invest. 117: 2459-2467, 2007. [PubMed: 17786239] [Full Text: https://doi.org/10.1172/JCI31960]
Pulipparacharuvil, S., Renthal, W., Hale, C. F., Taniguchi, M., Xiao, G., Kumar, A., Russo, S. J., Sikder, D., Dewey, C. M., Davis, M. M., Greengard, P., Nairn, A. C., Nestler, E. J., Cowan, C. W. Cocaine regulates MEF2 to control synaptic and behavioral plasticity. Neuron 59: 621-633, 2008. [PubMed: 18760698] [Full Text: https://doi.org/10.1016/j.neuron.2008.06.020]
Stumpf, A. M. Personal Communication. Baltimore, Md. 01/09/2020.
Yang, Q., She, H., Gearing, M., Colla, E., Lee, M., Shacka, J. J., Mao, Z. Regulation of neuronal survival factor MEF2D by chaperone-mediated autophagy. Science 323: 124-127, 2009. [PubMed: 19119233] [Full Text: https://doi.org/10.1126/science.1166088]