MYF5

Myogenic factor 5 is a protein that in humans is encoded by the MYF5 gene. [5] It is a protein with a key role in regulating muscle differentiation or myogenesis, specifically the development of skeletal muscle. Myf5 belongs to a family of proteins known as myogenic regulatory factors (MRFs). These basic helix loop helix transcription factors act sequentially in myogenic differentiation. MRF family members include Myf5, MyoD (Myf3), myogenin, and MRF4 (Myf6).[6] This transcription factor is the earliest of all MRFs to be expressed in the embryo, where it is only markedly expressed for a few days (specifically around 8 days post-somite formation and lasting until day 14 post-somite in mice).[7] It functions during that time to commit myogenic precursor cells to become skeletal muscle. In fact, its expression in proliferating myoblasts has led to its classification as a determination factor. Furthermore, Myf5 is a master regulator of muscle development, possessing the ability to induce a muscle phenotype upon its forced expression in fibroblastic cells.[8]

MYF5
Identifiers
AliasesMYF5, bHLHc2, myogenic factor 5, EORVA
External IDsOMIM: 159990 MGI: 97252 HomoloGene: 4085 GeneCards: MYF5
Gene location (Human)
Chr.Chromosome 12 (human)[1]
Band12q21.31Start80,716,912 bp[1]
End80,719,671 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

4617

17877

Ensembl

ENSG00000111049

ENSMUSG00000000435

UniProt

P13349

P24699

RefSeq (mRNA)

NM_005593

NM_008656

RefSeq (protein)

NP_005584

NP_032682

Location (UCSC)Chr 12: 80.72 – 80.72 MbChr 10: 107.48 – 107.49 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Expression

Myf5 is expressed in the dermomyotome of the early somites, pushing the myogenic precursors to undergo determination and differentiate into myoblasts.[7] Specifically, it is first seen in the dorsomedial portion of the dermomyotome, which develops into the epaxial myotome.[7] Although it is expressed in both the epaxial (to become muscles of the back) and hypaxial (body wall and limb muscles) portions of the myotome, it is regulated differently in these tissue lines, providing part of their alternative differentiation. Most notably, while Myf5 is activated by Sonic hedgehog in the epaxial lineage,[9] it is instead directly activated by the transcription factor Pax3 in hypaxial cells.[10] The limb myogenic precursors (derived from the hypaxial myotome) do not begin expressing Myf5 or any MRFs, in fact, until after migration to the limb buds.[11] Myf5 is also expressed in non-somitic paraxial mesoderm that forms muscles of the head, at least in zebrafish.[12]

While the product of this gene is capable of directing cells towards the skeletal muscle lineage, it is not absolutely required for this process. Numerous studies have shown redundancy with two other MRFs, MyoD and MRF4. The absence of all three of these factors results in a phenotype with no skeletal muscle.[13] These studies were performed after it was shown that Myf5 knockouts had no clear abnormality in their skeletal muscle.[14] The high redundancy of this system shows how crucial the development of skeletal muscle is to the viability of the fetus. Some evidence shows that Myf5 and MyoD are responsible for the development of separate muscle lineages, and are not expressed concurrently in the same cell.[15] Specifically, while Myf5 plays a large role in the initiation of epaxial development, MyoD directs the initiation of hypaxial development, and these separate lineages can compensate for the absence of one or the other. This has led some to claim that they are not indeed redundant, though this depends on the definition of the word. Still, the existence of these separate “MyoD-dependent” and “Myf5-dependent” subpopulations has been disputed, with some claiming that these MRFs are indeed coexpressed in muscle progenitor cells.[10] This debate is ongoing.

Although Myf5 is mainly associated with myogenesis, it is expressed in other tissues, as well. Firstly, it is expressed in brown adipose precursors. However, its expression is limited to brown and not white adipose precursors, providing part of the developmental separation between these two lineages.[16] Furthermore, Myf5 is expressed in portions of the neural tube (that go on to form neurons) a few days after it is seen in the somites. This expression is eventually repressed to prevent extraneous muscle formation.[17] Although the specific roles and dependency of Myf5 in adipogenesis and neurogenesis have remained to be explored, these findings show that Myf5 may play roles outside of myogenesis. Myf5 also has an indirect role controlling proximal rib development. Although Myf5 knockouts have normal skeletal muscle, they die due to abnormalities in their proximal ribs that make it difficult to breathe.[15]

Despite only being present for a few days during embryonic development, Myf5 is still expressed in certain adult cells. As one of the key cell markers of satellite cells (the stem cell pool for skeletal muscles), it plays an important role in the regeneration of adult muscle.[18] Specifically, it allows a brief pulse of proliferation of these satellite cells in response to injury. Differentiation begins (regulated by other genes) after this initial proliferation. In fact, if Myf5 is not downregulated, differentiation does not occur.[19]

In zebrafish, Myf5 is the first MRF expressed in embryonic myogenesis and is required for adult viability, even though larval muscle forms normally. As no muscle is formed in Myf5;Myod double mutant zebrafish, Myf5 cooperates with Myod to promote myogenesis.[20]

Regulation

The regulation of Myf5 is dictated by a large number of enhancer elements that allow a complex system of regulation. Although most events throughout myogenesis that involve Myf5 are controlled through the interaction of multiple enhancers, there is one important early enhancer that initiates expression. Termed the early epaxial enhancer, its activation provides the "go" signal for expression of Myf5 in the epaxial dermomyotome, where it is first seen.[21] Sonic hedgehog from the neural tube acts at this enhancer to activate it.[9] Following that, the chromosome contains different enhancers for regulation of Myf5 expression in the hypaxial region, cranial region, limbs, etc.[21] This early expression of Myf5 in the epaxial dermamyotome is involved with the very formation of myotome, but nothing beyond that. After its initial expression, other enhancer elements dictate where and how long it is expressed. It remains clear that each population of myogenic progenitor cells (for different locations in the embryo) is regulated by a different set of enhancers.[22]

Clinical significance

As for its clinical significance, the aberration of this transcription factor provides part of the mechanism for how hypoxia (lack of oxygen) can influence muscle development. Hypoxia has the ability to impede muscle differentiation in part by inhibiting the expression of Myf5 (as well as other MRFs). This prevents the muscle precursors from becoming post-mitotic muscle fibers. Although hypoxia is a teratogen, this inhibition of expression is reversible, therefore it remains unclear if there is a connection between hypoxia and birth defects in the fetus.[23]

References
  1. GRCh38: Ensembl release 89: ENSG00000111049 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000000435 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "Entrez Gene: Myogenic factor 5". Retrieved 2013-08-19.
  6. Sabourin LA, Rudnicki MA (January 2000). "The molecular regulation of myogenesis". Clinical Genetics. 57 (1): 16–25. doi:10.1034/j.1399-0004.2000.570103.x. PMID 10733231. S2CID 22496065.
  7. Ott MO, Bober E, Lyons G, Arnold H, Buckingham M (April 1991). "Early expression of the myogenic regulatory gene, myf-5, in precursor cells of skeletal muscle in the mouse embryo". Development. 111 (4): 1097–107. PMID 1652425.
  8. Braun T, Buschhausen-Denker G, Bober E, Tannich E, Arnold HH (March 1989). "A novel human muscle factor related to but distinct from MyoD1 induces myogenic conversion in 10T1/2 fibroblasts". The EMBO Journal. 8 (3): 701–9. doi:10.1002/j.1460-2075.1989.tb03429.x. PMC 400865. PMID 2721498.
  9. Gustafsson MK, Pan H, Pinney DF, Liu Y, Lewandowski A, Epstein DJ, Emerson CP (January 2002). "Myf5 is a direct target of long-range Shh signaling and Gli regulation for muscle specification". Genes & Development. 16 (1): 114–26. doi:10.1101/gad.940702. PMC 155306. PMID 11782449.
  10. Tajbakhsh S, Rocancourt D, Cossu G, Buckingham M (April 1997). "Redefining the genetic hierarchies controlling skeletal myogenesis: Pax-3 and Myf-5 act upstream of MyoD". Cell. 89 (1): 127–38. doi:10.1016/s0092-8674(00)80189-0. PMID 9094721. S2CID 18747744.
  11. Tajbakhsh S, Buckingham ME (January 1994). "Mouse limb muscle is determined in the absence of the earliest myogenic factor myf-5". Proceedings of the National Academy of Sciences of the United States of America. 91 (2): 747–51. Bibcode:1994PNAS...91..747T. doi:10.1073/pnas.91.2.747. PMC 43026. PMID 8290594.
  12. Lin CY, Yung RF, Lee HC, Chen WT, Chen YH, Tsai HJ (November 2006). "Myogenic regulatory factors Myf5 and Myod function distinctly during craniofacial myogenesis of zebrafish". Developmental Biology. 299 (2): 594–608. doi:10.1016/j.ydbio.2006.08.042. PMID 17007832.
  13. Kassar-Duchossoy L, Gayraud-Morel B, Gomès D, Rocancourt D, Buckingham M, Shinin V, Tajbakhsh S (September 2004). "Mrf4 determines skeletal muscle identity in Myf5:Myod double-mutant mice". Nature. 431 (7007): 466–71. Bibcode:2004Natur.431..466K. doi:10.1038/nature02876. PMID 15386014. S2CID 4413512.
  14. Rudnicki MA, Schnegelsberg PN, Stead RH, Braun T, Arnold HH, Jaenisch R (December 1993). "MyoD or Myf-5 is required for the formation of skeletal muscle". Cell. 75 (7): 1351–9. doi:10.1016/0092-8674(93)90621-v. PMID 8269513. S2CID 27322641.
  15. Haldar M, Karan G, Tvrdik P, Capecchi MR (March 2008). "Two cell lineages, myf5 and myf5-independent, participate in mouse skeletal myogenesis". Developmental Cell. 14 (3): 437–45. doi:10.1016/j.devcel.2008.01.002. PMC 2917991. PMID 18331721.
  16. Timmons JA, Wennmalm K, Larsson O, Walden TB, Lassmann T, Petrovic N, Hamilton DL, Gimeno RE, Wahlestedt C, Baar K, Nedergaard J, Cannon B (March 2007). "Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages". Proceedings of the National Academy of Sciences of the United States of America. 104 (11): 4401–6. Bibcode:2007PNAS..104.4401T. doi:10.1073/pnas.0610615104. PMC 1810328. PMID 17360536.
  17. Tajbakhsh S, Buckingham ME (December 1995). "Lineage restriction of the myogenic conversion factor myf-5 in the brain". Development. 121 (12): 4077–83. PMID 8575308.
  18. Beauchamp JR, Heslop L, Yu DS, Tajbakhsh S, Kelly RG, Wernig A, Buckingham ME, Partridge TA, Zammit PS (December 2000). "Expression of CD34 and Myf5 defines the majority of quiescent adult skeletal muscle satellite cells". The Journal of Cell Biology. 151 (6): 1221–34. doi:10.1083/jcb.151.6.1221. PMC 2190588. PMID 11121437.
  19. Ustanina S, Carvajal J, Rigby P, Braun T (August 2007). "The myogenic factor Myf5 supports efficient skeletal muscle regeneration by enabling transient myoblast amplification". Stem Cells. 25 (8): 2006–16. doi:10.1634/stemcells.2006-0736. PMID 17495111. S2CID 28853682.
  20. Hinits Y, Williams VC, Sweetman D, Donn TM, Ma TP, Moens CB, Hughes SM (2011). "Defective cranial skeletal development, larval lethality and haploinsufficiency in Myod mutant zebrafish". Developmental Biology. 358 (1): 102–12. doi:10.1016/j.ydbio.2011.07.015. PMC 3360969. PMID 21798255.
  21. Summerbell D, Ashby PR, Coutelle O, Cox D, Yee S, Rigby PW (September 2000). "The expression of Myf5 in the developing mouse embryo is controlled by discrete and dispersed enhancers specific for particular populations of skeletal muscle precursors". Development. 127 (17): 3745–57. PMID 10934019.
  22. Teboul L, Hadchouel J, Daubas P, Summerbell D, Buckingham M, Rigby PW (October 2002). "The early epaxial enhancer is essential for the initial expression of the skeletal muscle determination gene Myf5 but not for subsequent, multiple phases of somitic myogenesis". Development. 129 (19): 4571–80. PMID 12223413.
  23. Di Carlo A, De Mori R, Martelli F, Pompilio G, Capogrossi MC, Germani A (April 2004). "Hypoxia inhibits myogenic differentiation through accelerated MyoD degradation". The Journal of Biological Chemistry. 279 (16): 16332–8. doi:10.1074/jbc.M313931200. PMID 14754880.

Further reading
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