Disease relevance of Myf6

• We report the first mouse model of alveolar rhabdomyosarcoma using a conditional Pax3:Fkhr knock-in allele whose activation in late embryogenesis and postnatally is targeted to terminally differentiating Myf6-expressing skeletal muscle [1].
• When expressed under the control of the simian virus 40 early promoter, transfected herculin renders murine NIH 3T3 and C3H/10T1/2 fibroblasts myogenic [2].

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

• This suggests that Myf-6 has no major role in the maturation of myotubes, as previously proposed [8].
• These results suggest that early Myf-6 expression may be restricted to a population of myogenic cells that does not contribute to the embryonic muscle masses in limb buds and visceral arches [9].
• In adult mice, herculin is expressed in skeletal muscle but is absent from smooth muscle, cardiac muscle, and all nonmuscle tissues assayed [2].
• These mice appear to contain a normal number of myoblasts, but in contrast to myogenin or MyoD/MRF4 mutants, differentiated muscle fibers fail to form in vivo and myoblasts from neonates of this triple-mutant genotype are unable to differentiate in vitro [10].
• BC3H-1 cells that stably expressed exogenous MRF4 were prepared and termed BR cell lines [11].

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

• To test the importance of MRF4 in Na(V) 1.4 gene regulation in vivo, we examined Na+ channel expression in MRF4-null mice using several techniques, including Western blotting, immunocytochemistry, and electrophysiological recording [23].
• Gene targeting studies have revealed hierarchical relationships between these and the other MRF genes, Mrf4 and myogenin, where the latter are regarded as differentiation genes [24].
• We have now investigated the transcriptional regulation of both Myf5 and Mrf4 using bacterial artificial chromosome transgenesis [25].
• Denervation induces a rapid nuclear accumulation of MRF4 in mature myofibers [26].
• In contrast, any of these three immunologic techniques readily detected MRF4 immunoreactivity in myofiber and satellite cell nuclei of muscles denervated for 24 hours [26].

References