Disease relevance of Myf5

• We showed that hypoxia reversibly inhibited MyoD, Myf5, and myogenin expression [1].

High impact information on Myf5

• We have used this procedure to describe the cardiac phenotype and associated blood vessels of trisomic 16 (Ts16) and Cited2-null mutant mice, as well as the expression pattern of an Myf5 enhancer/beta-galactosidase transgene [2].
• Myf-5 revisited: loss of early myotome formation does not lead to a rib phenotype in homozygous Myf-5 mutant mice [3].
• Remarkably, splotch/Myf-5 double homozygotes have a dramatic phenotype not seen in the individual mutants: body muscles are absent [4].
• Therefore, Pax-3 and Myf-5 define two distinct myogenic pathways, and MyoD acts genetically downstream of these genes for myogenesis in the body [4].
• In splotch and Myf-5 homozygous embryos, myogenic progenitor cell perturbations and early muscle defects are distinct [4].

Biological context of Myf5

• This data implicates CD34 in the maintenance of satellite cell quiescence.In heterozygous Myf5(nlacZ/+) mice, all CD34(+ve) satellite cells also express beta-galactosidase, a marker of activation of Myf5, showing that quiescent satellite cells are committed to myogenesis [5].
• We have used microarray and polymerase chain reaction approaches to measure the induction of muscle gene expression by MyoD and Myf5 in an in vitro model [6].
• MyoD and Myf5 are basic helix-loop-helix transcription factors that play key but redundant roles in specifying myogenic progenitors during embryogenesis [6].
• We propose that the first phase of Myf5 epaxial expression, driven by the early epaxial enhancer in the dermomyotome, is necessary for early myotome formation, while the subsequent phases are associated with cytodifferentiation within the myotome [7].
• In the mouse limb bud, the Msx1(nlacZ )transgene is downregulated prior to the activation of the Myf5 gene, an early marker of myogenic differentiation [8].

Anatomical context of Myf5

• Genetic studies have demonstrated that MyoD and Myf5 establish the skeletal muscle lineage, whereas myogenin mediates terminal differentiation, yet the molecular basis for this distinction is not understood [9].
• Together, these results support the notion that Myf5 functions toward myoblast proliferation, whereas MyoD prepares myoblasts for efficient differentiation [6].
• Here we describe two novel markers of quiescent satellite cells: CD34, an established marker of hematopoietic stem cells, and Myf5, the earliest marker of myogenic commitment [5].
• Myf5 expression is correctly initiated but becomes restricted to the caudal region of each somite [10].
• Shh is not required for the activation of Myf5 and MyoD at any of the other sites of myogenesis in the mouse embryo, including the hypaxial dermomyotomal cells that give rise to the abdominal and body wall muscles, or the myogenic progenitor cells that form the limb and head muscles [11].

Associations of Myf5 with chemical compounds

• This distinction between MyoD and Myf5 results from a novel and unanticipated cooperation between the MyoD NH2- and COOH-terminal regions [6].
• Unlike wild-type myogenic precursor cells, Myf5-null cells do not express the alpha6beta1 integrin, a laminin receptor, suggesting that integrin alpha6beta1-laminin interactions are required for myotomal laminin matrix assembly [12].
• We report here that retinoic acid (RA) reduces the level of Myf5 message in both mouse C2 and rat L6 cell lines, probably at the transcriptional level, because Myf5 mRNA stability is not affected by RA [13].
• 9-cis-retinoic acid regulates the expression of the muscle determination gene Myf5 [13].
• This repression is dose dependent, starting at 0.1 microM of all-trans RA, and is not abrogated by cycloheximide, suggesting a direct involvement of RA receptors in the control of Myf5 expression [13].

Physical interactions of Myf5

• In previous studies, we showed that Shh signalling, via an essential Gli-binding site in the Myf5 epaxial somite (ES) enhancer, is required for the specification of epaxial muscle progenitor cells [14].

Regulatory relationships of Myf5

• Sonic hedgehog controls epaxial muscle determination through Myf5 activation [11].
• Pax3 lies genetically upstream of MyoD and has also been shown recently to directly control Myf5 transcription in derivatives of the hypaxial somite, where it also plays an important role in ensuring cell survival [15].
• 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 [16].
• Myf5 is the first gene to be expressed followed by myogenin, myoD, and myf6, in this order [17].
• As 9-cis RA is about 10 times more efficient than all-trans RA in repressing Myf5, whereas TTNPB, which preferentially activates RA receptors, is far less potent, our data provide evidence for an important role of ligand-bound retinoid X-receptors in the mediation of this inhibition [13].
• Six1/4 therefore regulate Myf5 transcription, together with Pax3, which was previously shown to be required for the activity of the 145-bp element [18].

Other interactions of Myf5

• Homozygous mice carrying the disrupted Myf-6 gene show pronounced down-regulation of Myf-5 transcription for reasons presently unknown [19].
• We also showed that the endogenous neuronal differentiation program is inhibited under the influence of either ectopic mouse Myf5 or MyoD [20].
• Myogenin can substitute for Myf5 in promoting myogenesis but less efficiently [21].
• At Theiler stage 17 (day 10.5 post coitum) of development, strongly altered expression patterns of Pax3 and Myf5 were observed in dorsal somite regions indicating that the dorsal myotome and dermomyotome were not differentiating properly [22].
• We conclude, therefore, that Shh has multiple functions in the somite, including inductive functions in the activation of Myf5, leading to the determination of epaxial dermomyotomal cells to myogenesis, as well as trophic functions in the maintenance of cell survival in the sclerotome and adjacent neural tube [11].

Analytical, diagnostic and therapeutic context of Myf5

• To investigate the role of Myf5 in the brain, we monitored Myf5 protein accumulation by immunofluorescence and immunoblotting in neurons transcribing the gene [23].
• We have taken advantage of the chick model to investigate the effect of electroporation of the mouse Myf5 and MyoD genes in the embryonic neural tube [20].
• RT-PCR experiments show that the splicing of Myf5 primary transcripts occurs correctly in neurons, suggesting that the lack of Myf5 protein accumulation is due to regulation at the level of mRNA translation or protein stability [23].
• The expression pattern of myogenic regulatory factors and myotome-specific contractile proteins was studied during embryonic development of Myf-5 mutant mice by in situ hybridization and immunohistochemistry [24].
• We have now investigated the transcriptional regulation of both Myf5 and Mrf4 using bacterial artificial chromosome transgenesis [25].

References