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Gene Review

Myf6  -  myogenic factor 6

Mus musculus

Synonyms: Herculin, MRF4, Mrf4, Muscle-specific regulatory factor 4, Myf-6, ...
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Disease relevance of Myf6


Psychiatry related information on Myf6

  • There was also a transient twofold increase in mrf4 transcripts by dexamethasone treatment in dividing cells, while no changes were detected in the levels of Id, E12, or TnC messages [3].

High impact information on Myf6

  • Know your neighbors: three phenotypes in null mutants of the myogenic bHLH gene MRF4 [4].
  • Northern blot analysis demonstrated normal levels of muscle-specific mRNAs including MyoD, myogenin, and Myf-6 [5].
  • Myogenin and MRF4 have later functions in muscle differentiation, and Pax and Hox genes coordinate the migration and specification of somite progenitors at sites of hypaxial and limb muscle formation in the embryo body [6].
  • Inactivation of the myogenic bHLH gene MRF4 results in up-regulation of myogenin and rib anomalies [7].
  • On the basis of its expression pattern, it has been proposed that MRF4 may regulate skeletal muscle maturation and aspects of adult myogenesis [7].

Biological context of Myf6

  • We disrupted the Myf-6 gene in mice to investigate its functional role in the network of regulatory factors controlling myogenesis [8].
  • Homozygous mice carrying the disrupted Myf-6 gene show pronounced down-regulation of Myf-5 transcription for reasons presently unknown [8].
  • Myf-6 transcripts are first detected in the most rostral somites of the mouse embryo at 9 d of gestation and accumulate progressively in myotomal cells along the rostro-caudal axis [9].
  • A putative 27-kDa protein is encoded by three exons contained within a 1.7-kilobase fragment of the herculin gene [2].
  • The herculin gene is physically linked to the Myf-5 gene on the chromosome; only 8.5 kilobases separate their translational start sites [2].

Anatomical context of Myf6


Associations of Myf6 with chemical compounds

  • The spatial and temporal expression pattern of the muscle regulatory gene Myf-6 (MRF4/herculin) has been investigated by in situ hybridization during embryonic and fetal mouse development [9].
  • Of particular interest was the finding that expression of MRF4 was temporally correlated with expression of the gene for the acetylcholine receptor epsilon-subunit that is characteristic of the adult receptor [12].
  • Our results indicate that MRF4 is phosphorylated predominantly on serine residues, with weak phosphorylation occurring on threonine residues [13].
  • Both cyclic AMP-dependent protein kinase (PKA) and protein kinase C (PKC) phosphorylate MRF4 in vitro as well as in vivo, and the overexpression of each kinase inhibits MRF4 activity and thus blocks terminal differentiation [13].
  • T3 and retinoids have been demonstrated to promote terminal muscle differentiation via activation of the muscle specific myoD gene family (myoD, myogenin, myf-5 and MRF-4) [14].

Regulatory relationships of Myf6

  • This possibility was first raised by the observation that the most severe MRF4 knockout allele expresses no Myf-5 RNA and is a developmental phenocopy of the Myf-5 null mutation [15].
  • These results demonstrate that MRF4 is able to substitute for myogenin to activate MRF4 expression and promote myofiber formation during the early stages of myogenesis [16].
  • Thus, the MRF4 promoter is regulated by the MEF2 and basic helix-loop-helix MRF protein family through a cross-regulatory circuitry [17].
  • Consistent with this finding, the RECK-promoter is activated by MRF4 in cultured cells [18].
  • Here, we confirm the distinction between myogenin and MyoD using another expression vector and show that constitutively expressed MRF4 leads to myofiber formation in myogenin's absence [19].

Other interactions of Myf6

  • The onset of MyoD expression around E10.5 in wild-type embryos marks a third myotomal program (My3), the execution of which was somewhat delayed in MRF4 mutant embryos but ultimately led to extensive myogenesis in the trunk [20].
  • In the hind limb bud myf5, myogenin, and MRF4 expression was detected 11.5 dpc [21].
  • Northern analysis revealed delayed induction of myogenin, MRF4, and other differentiation-specific markers although p21 was upregulated normally [22].
  • Located within the proximal promoter are a single MEF2 site and E box that are required for maximum MRF4 expression [17].
  • In the present study, we have found that in later stage wild-type embryos, RECK is abundantly expressed in skeletal muscles, especially in the areas where the myoblast differentiation factor MRF4 is expressed [18].

Analytical, diagnostic and therapeutic context of Myf6


  1. Alveolar rhabdomyosarcomas in conditional Pax3:Fkhr mice: cooperativity of Ink4a/ARF and Trp53 loss of function. Keller, C., Arenkiel, B.R., Coffin, C.M., El-Bardeesy, N., DePinho, R.A., Capecchi, M.R. Genes Dev. (2004) [Pubmed]
  2. Herculin, a fourth member of the MyoD family of myogenic regulatory genes. Miner, J.H., Wold, B. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  3. Dexamethasone-mediated induction of MMTV-myf5 in DD3 myoblasts increases endogenous myogenin expression but does not transactivate myf5. Arnold, T.E., Worrell, R.A., Barth, J.L., Morris, J., Ivarie, R. Exp. Cell Res. (1994) [Pubmed]
  4. Know your neighbors: three phenotypes in null mutants of the myogenic bHLH gene MRF4. Olson, E.N., Arnold, H.H., Rigby, P.W., Wold, B.J. Cell (1996) [Pubmed]
  5. Targeted inactivation of the muscle regulatory gene Myf-5 results in abnormal rib development and perinatal death. Braun, T., Rudnicki, M.A., Arnold, H.H., Jaenisch, R. Cell (1992) [Pubmed]
  6. Myogenic regulatory factors and the specification of muscle progenitors in vertebrate embryos. Pownall, M.E., Gustafsson, M.K., Emerson, C.P. Annu. Rev. Cell Dev. Biol. (2002) [Pubmed]
  7. Inactivation of the myogenic bHLH gene MRF4 results in up-regulation of myogenin and rib anomalies. Zhang, W., Behringer, R.R., Olson, E.N. Genes Dev. (1995) [Pubmed]
  8. Inactivation of Myf-6 and Myf-5 genes in mice leads to alterations in skeletal muscle development. Braun, T., Arnold, H.H. EMBO J. (1995) [Pubmed]
  9. The muscle regulatory gene, Myf-6, has a biphasic pattern of expression during early mouse development. Bober, E., Lyons, G.E., Braun, T., Cossu, G., Buckingham, M., Arnold, H.H. J. Cell Biol. (1991) [Pubmed]
  10. Failure of Myf5 to support myogenic differentiation without myogenin, MyoD, and MRF4. Valdez, M.R., Richardson, J.A., Klein, W.H., Olson, E.N. Dev. Biol. (2000) [Pubmed]
  11. Expression of MRF4, a myogenic helix-loop-helix protein, produces multiple changes in the myogenic program of BC3H-1 cells. Block, N.E., Miller, J.B. Mol. Cell. Biol. (1992) [Pubmed]
  12. Developmental patterns in the expression of Myf5, MyoD, myogenin, and MRF4 during myogenesis. Montarras, D., Chelly, J., Bober, E., Arnold, H., Ott, M.O., Gros, F., Pinset, C. New Biol. (1991) [Pubmed]
  13. Fibroblast growth factor inhibits MRF4 activity independently of the phosphorylation status of a conserved threonine residue within the DNA-binding domain. Hardy, S., Kong, Y., Konieczny, S.F. Mol. Cell. Biol. (1993) [Pubmed]
  14. Identification of a regulatory function for an orphan receptor in muscle: COUP-TF II affects the expression of the myoD gene family during myogenesis. Muscat, G.E., Rea, S., Downes, M. Nucleic Acids Res. (1995) [Pubmed]
  15. Different MRF4 knockout alleles differentially disrupt Myf-5 expression: cis-regulatory interactions at the MRF4/Myf-5 locus. Yoon, J.K., Olson, E.N., Arnold, H.H., Wold, B.J. Dev. Biol. (1997) [Pubmed]
  16. MRF4 can substitute for myogenin during early stages of myogenesis. Zhu, Z., Miller, J.B. Dev. Dyn. (1997) [Pubmed]
  17. Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis. Naidu, P.S., Ludolph, D.C., To, R.Q., Hinterberger, T.J., Konieczny, S.F. Mol. Cell. Biol. (1995) [Pubmed]
  18. The membrane-anchored MMP-regulator RECK is a target of myogenic regulatory factors. Echizenya, M., Kondo, S., Takahashi, R., Oh, J., Kawashima, S., Kitayama, H., Takahashi, C., Noda, M. Oncogene (2005) [Pubmed]
  19. Similar myogenic functions for myogenin and MRF4 but not MyoD in differentiated murine embryonic stem cells. Sumariwalla, V.M., Klein, W.H. Genesis (2001) [Pubmed]
  20. Disruption of the mouse MRF4 gene identifies multiple waves of myogenesis in the myotome. Patapoutian, A., Yoon, J.K., Miner, J.H., Wang, S., Stark, K., Wold, B. Development (1995) [Pubmed]
  21. Temporal and quantitative analysis of myogenic regulatory and growth factor gene expression in the developing mouse embryo. Hannon, K., Smith, C.K., Bales, K.R., Santerre, R.F. Dev. Biol. (1992) [Pubmed]
  22. Reduced differentiation potential of primary MyoD-/- myogenic cells derived from adult skeletal muscle. Sabourin, L.A., Girgis-Gabardo, A., Seale, P., Asakura, A., Rudnicki, M.A. J. Cell Biol. (1999) [Pubmed]
  23. A selective role for MRF4 in innervated adult skeletal muscle: Na(V) 1.4 Na+ channel expression is reduced in MRF4-null mice. Thompson, A.L., Filatov, G., Chen, C., Porter, I., Li, Y., Rich, M.M., Kraner, S.D. Gene Expr. (2005) [Pubmed]
  24. Mrf4 determines skeletal muscle identity in Myf5:Myod double-mutant mice. Kassar-Duchossoy, L., Gayraud-Morel, B., Gomès, D., Rocancourt, D., Buckingham, M., Shinin, V., Tajbakhsh, S. Nature (2004) [Pubmed]
  25. A BAC transgenic analysis of the Mrf4/Myf5 locus reveals interdigitated elements that control activation and maintenance of gene expression during muscle development. Carvajal, J.J., Cox, D., Summerbell, D., Rigby, P.W. Development (2001) [Pubmed]
  26. Denervation induces a rapid nuclear accumulation of MRF4 in mature myofibers. Weis, J., Kaussen, M., Calvo, S., Buonanno, A. Dev. Dyn. (2000) [Pubmed]
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