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Looking back to the embryo: defining transcriptional networks in adult myogenesis

Nature Reviews Genetics volume 4, pages 497–507 (2003)Cite this article

Key Points

  • In response to muscle damage, specialized adult myogenic progenitors known as satellite cells activate a myogenic transcriptional programme, which is analogous to that induced during embryonic and fetal muscle development.

  • Either MyoD or Myf5 is required for the commitment of skeletal myogenic cells; in the absence of both transcription factors, progenitor cells assume non-muscle fates.

  • Pax3 and Myf5 function upstream of MyoD in embryonic myogenesis. Pax3 is required for the proliferation, survival and specification of stem cells in the pre-somitic mesoderm.

  • Shh directly activates Myf5 transcription through specific Gli1 binding sites in the epaxial somite enhancer.

  • Activation of several signalling pathways — including the Wnt, Hedgehog, BMP and Notch cascades — determines the balance between the determination, proliferation, survival and differentiation of muscle progenitors in the somite.

  • Pax7 is required for the development of adult muscle satellite cells that function in the postnatal growth and repair of skeletal muscle fibers.

  • MyoD is required for adult muscle regeneration by promoting the myogenic differentiation of satellite-cell derived myoblasts.

  • The activation or modulation of signalling pathways that are implicated in embryonic and fetal muscle formation might provide a useful therapeutic strategy for the generation of muscle cells from adult stem cells either in vivo or ex vivo.

Abstract

Skeletal muscle has an intrinsic capacity for regeneration following injury or exercise. The presence of adult stem cells in various tissues with myogenic potential provides new opportunities for cell-based therapies to treat muscle disease. Recent studies have shown a conserved transcriptional hierarchy that regulates the myogenic differentiation of both embryonic and adult stem cells. Importantly, the molecules and signalling pathways that induce myogenic determination in the embryo might be manipulated or mimicked to direct the differentiation of adult stem cells either in vivo or ex vivo.

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Figure 1: The embryonic origin of limb and trunk skeletal muscle.
Figure 2: The pathways that regulate Myf5 and MyoD expression.
Figure 3: Muscle satellite cells express Pax7.
Figure 4: Regenerative myogenesis in the adult.

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References

  1. Ferrari, G. et al. Muscle regeneration by bone marrow-derived myogenic progenitors. Science 279, 1528–1530 (1998). This seminal study documents the capacity for transplanted bone-marrow cells from transgenic mice to migrate to sites of muscle degeneration and differentiate into muscle. This report proposes the possibility that bone-marrow cells might be used as a source of myogenic progenitors to treat muscle disease.

    Article  CAS  PubMed  Google Scholar 

  2. La Barge, M. A. & Blau, H. M. Biological progression from adult bone marrow to mononucleate muscle stem cell to multinucleate muscle fiber in response to injury. Cell 111, 589–601 (2002). This important work shows that transplanted bone-marrow cells can give rise to satellite cells after exercise-induced regeneration. This indicates that marrow-derived differentiation into non-hematopoeitic tissues might be mediated through a tissue-specific stem-cell intermediate, such as the muscle satellite cell.

    Article  CAS  Google Scholar 

  3. Summerbell, D. & Rigby, P. W. Transcriptional regulation during somitogenesis. Curr. Top. Dev. Biol. 48, 301–318 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Pourquie, O. Vertebrate somitogenesis. Annu. Rev. Cell. Dev. Biol. 17, 311–350 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Pownall, M. E., Gustafsson, M. K. & Emerson, C. P. Myogenic regulatory factors and the specification of muscle progenitors in vertebrate embryos. Annu. Rev. Cell. Dev. Biol. 18, 747–783 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Brent, A. E., Schweitzer, R. & Tabin, C. J. A somitic compartment of tendon progenitors. Cell 113, 235–248 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Jostes, B., Walther, C. & Gruss, P. The murine paired box gene, Pax7, is expressed specifically during the development of the nervous and muscular system. Mech. Dev. 33, 27–37 (1990).

    Article  CAS  PubMed  Google Scholar 

  8. Goulding, M., Lumsden, A. & Paquette, A. J. Regulation of Pax-3 expression in the dermomyotome and its role in muscle development. Development 120, 957–971 (1994).

    Article  CAS  PubMed  Google Scholar 

  9. Kiefer, J. C. & Hauschka, S. D. Myf-5 is transiently expressed in nonmuscle mesoderm and exhibits dynamic regional changes within the presegmented mesoderm and somites I–IV. Dev. Biol. 232, 77–90 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Hirsinger, E. et al. Notch signalling acts in postmitotic avian myogenic cells to control MyoD activation. Development 128, 107–116 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Amthor, H., Christ, B. & Patel, K. A molecular mechanism enabling continuous embryonic muscle growth — a balance between proliferation and differentiation. Development 126, 1041–1053 (1999). This paper proposes the hypothesis that embryonic myogenesis requires a temporal balance between proliferation and differentiation that is achieved through the presence of external cues, such as BMP and Shh signalling, and regulation of the expression of Pax3 and MyoD.

    Article  CAS  PubMed  Google Scholar 

  12. Christ, B. & Ordahl, C. P. Early stages of chick somite development. Anat. Embryol. 191, 381–396 (1995).

    Article  CAS  Google Scholar 

  13. Ordahl, C. P. & Le Douarin, N. M. Two myogenic lineages within the developing somite. Development 114, 339–353 (1992).

    Article  CAS  PubMed  Google Scholar 

  14. Puri, P. L. & Sartorelli, V. Regulation of muscle regulatory factors by DNA-binding, interacting proteins, and post-transcriptional modifications. J. Cell. Physiol. 185, 155–173 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Perry, R. L. & Rudnick, M. A. Molecular mechanisms regulating myogenic determination and differentiation. Front. Biosci. 5, D750–D767 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Bergstrom, D. A. & Tapscott, S. J. Molecular distinction between specification and differentiation in the myogenic basic helix–loop–helix transcription factor family. Mol. Cell. Biol. 21, 2404–2412 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Naya, F. J., Wu, C., Richardson, J. A., Overbeek, P. & Olson, E. N. Transcriptional activity of MEF2 during mouse embryogenesis monitored with a MEF2-dependent transgene. Development 126, 2045–2052 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Naya, F. S. & Olson, E. MEF2: a transcriptional target for signaling pathways controlling skeletal muscle growth and differentiation. Curr. Opin. Cell. Biol. 11, 683–688 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Naidu, P. S., Ludolph, D. C., To, R. Q., Hinterberger, T. J. & Konieczny, S. F. Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis. Mol. Cell. Biol. 15, 2707–2718 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ridgeway, A. G., Wilton, S. & Skerjanc, I. S. Myocyte enhancer factor 2C and myogenin up-regulate each other's expression and induce the development of skeletal muscle in P19 cells. J. Biol. Chem. 275, 41–46 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Novitch, B. G., Mulligan, G. J., Jacks, T. & Lassar, A. B. Skeletal muscle cells lacking the retinoblastoma protein display defects in muscle gene expression and accumulate in S and G2 phases of the cell cycle. J. Cell. Biol. 135, 441–456 (1996).

    Article  CAS  PubMed  Google Scholar 

  22. Novitch, B. G., Spicer, D. B., Kim, P. S., Cheung, W. L. & Lassar, A. B. pRb is required for MEF2-dependent gene expression as well as cell-cycle arrest during skeletal muscle differentiation. Curr. Biol. 9, 449–459 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Lin, J. et al. Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres. Nature 418, 797–801 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Kablar, B. et al. Myogenic determination occurs independently in somites and limb buds. Dev. Biol. 206, 219–231 (1999).

    Article  CAS  PubMed  Google Scholar 

  25. Tajbakhsh, S., Rocancourt, D. & Buckingham, M. Muscle progenitor cells failing to respond to positional cues adopt non-myogenic fates in myf-5 null mice. Nature 384, 266–270 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. Kablar, B. et al. MyoD and Myf-5 differentially regulate the development of limb versus trunk skeletal muscle. Development 124, 4729–4738 (1997).

    Article  CAS  PubMed  Google Scholar 

  27. Ordahl, C. P. & Williams, B. A. Knowing chops from chuck: roasting myoD redundancy. Bioessays 20, 357–362 (1998).

    Article  CAS  PubMed  Google Scholar 

  28. Hasty, P. et al. Muscle deficiency and neonatal death in mice with a targeted mutation in the myogenin gene. Nature 364, 501–506 (1993).

    Article  CAS  PubMed  Google Scholar 

  29. Nabeshima, Y. et al. Myogenin gene disruption results in perinatal lethality because of severe muscle defect. Nature 364, 532–535 (1993).

    Article  CAS  PubMed  Google Scholar 

  30. Braun, T. & Arnold, H. H. Inactivation of Myf-6 and Myf-5 genes in mice leads to alterations in skeletal muscle development. EMBO J. 14, 1176–1186 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Patapoutian, A. et al. Disruption of the mouse MRF4 gene identifies multiple waves of myogenesis in the myotome. Development 121, 3347–3358 (1995).

    Article  CAS  PubMed  Google Scholar 

  32. Zhang, W., Behringer, R. R. & Olson, E. N. Inactivation of the myogenic bHLH gene MRF4 results in up-regulation of myogenin and rib anomalies. Genes Dev. 9, 1388–1399 (1995).

    Article  CAS  PubMed  Google Scholar 

  33. Tajbakhsh, S. et al. Gene targeting the myf-5 locus with nlacZ reveals expression of this myogenic factor in mature skeletal muscle fibres as well as early embryonic muscle. Dev. Dyn. 206, 291–300 (1996).

    Article  CAS  PubMed  Google Scholar 

  34. Carvajal, J. J., Cox, D., Summerbell, D. & Rigby, P. W. A BAC transgenic analysis of the Mrf4/Myf5 locus reveals interdigitated elements that control activation and maintenance of gene expression during muscle development. Development 128, 1857–1868 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Hadchouel, J. et al. Modular long-range regulation of Myf5 reveals unexpected heterogeneity between skeletal muscles in the mouse embryo. Development 127, 4455–4467 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Summerbell, D. et al. 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, 3745–3757 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Sporle, R., Gunther, T., Struwe, M. & Schughart, K. Severe defects in the formation of epaxial musculature in open brain (opb) mutant mouse embryos. Development 122, 79–86 (1996).

    Article  CAS  PubMed  Google Scholar 

  38. Dietrich, S., Schubert, F. R., Gruss, P. & Lumsden, A. The role of the notochord for epaxial myotome formation in the mouse. Cell. Mol. Biol. 45, 601–616 (1999).

    CAS  PubMed  Google Scholar 

  39. Asakura, A. & Tapscott, S. J. Apoptosis of epaxial myotome in Danforth's short-tail (Sd) mice in somites that form following notochord degeneration. Dev. Biol. 203, 276–289 (1998).

    Article  CAS  PubMed  Google Scholar 

  40. Borycki, A. G. et al. Sonic hedgehog controls epaxial muscle determination through Myf5 activation. Development 126, 4053–4063 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Gustafsson, M. K. et al. Myf5 is a direct target of long-range Shh signaling and Gli regulation for muscle specification. Genes Dev. 16, 114–126 (2002). This study is the first to provide a direct association between environmental cues that regulate myogenesis and the activation of a muscle-specification gene. Specifically, the authors show that long-range Shh signalling activates Myf5 through Gli1 binding sites in the Myf5 epaxial somite enhancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Chiang, C. et al. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383, 407–413 (1996).

    Article  CAS  PubMed  Google Scholar 

  43. Kruger, M. et al. Sonic hedgehog is a survival factor for hypaxial muscles during mouse development. Development 128, 743–752 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Duprez, D., Fournier-Thibault, C. & Le Douarin, N. Sonic Hedgehog induces proliferation of committed skeletal muscle cells in the chick limb. Development 125, 495–505 (1998).

    Article  CAS  PubMed  Google Scholar 

  45. Pourquie, O., Coltey, M., Breant, C. & Le Douarin, N. M. Control of somite patterning by signals from the lateral plate. Proc. Natl Acad. Sci. USA 92, 3219–3223 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Pourquie, O. et al. Lateral and axial signals involved in avian somite patterning: a role for BMP4. Cell 84, 461–471 (1996).

    Article  CAS  PubMed  Google Scholar 

  47. Cossu, G. et al. Activation of different myogenic pathways: myf-5 is induced by the neural tube and MyoD by the dorsal ectoderm in mouse paraxial mesoderm. Development 122, 429–437 (1996).

    Article  CAS  PubMed  Google Scholar 

  48. Tajbakhsh, S. et al. Differential activation of Myf5 and MyoD by different Wnts in explants of mouse paraxial mesoderm and the later activation of myogenesis in the absence of Myf5. Development 125, 4155–4162 (1998).

    Article  CAS  PubMed  Google Scholar 

  49. Borello, U. et al. Transplacental delivery of the Wnt antagonist Frzb1 inhibits development of caudal paraxial mesoderm and skeletal myogenesis in mouse embryos. Development 126, 4247–4255 (1999).

    Article  CAS  PubMed  Google Scholar 

  50. Amthor, H., Christ, B., Weil, M. & Patel, K. The importance of timing differentiation during limb muscle development. Curr. Biol. 8, 642–652 (1998).

    Article  CAS  PubMed  Google Scholar 

  51. Dietrich, S., Schubert, F. R., Healy, C., Sharpe, P. T. & Lumsden, A. Specification of the hypaxial musculature. Development 125, 2235–2249 (1998).

    Article  CAS  PubMed  Google Scholar 

  52. Hirsinger, E. et al. Noggin acts downstream of Wnt and Sonic Hedgehog to antagonize BMP4 in avian somite patterning. Development 124, 4605–4614 (1997).

    Article  CAS  PubMed  Google Scholar 

  53. Reshef, R., Maroto, M. & Lassar, A. B. Regulation of dorsal somitic cell fates: BMPs and Noggin control the timing and pattern of myogenic regulator expression. Genes Dev. 12, 290–303 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. McMahon, J. A. et al. Noggin-mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite. Genes Dev. 12, 1438–1452 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Delfini, M., Hirsinger, E., Pourquie, O. & Duprez, D. δ1-activated notch inhibits muscle differentiation without affecting Myf5 and Pax3 expression in chick limb myogenesis. Development 127, 5213–5224 (2000).

    Article  CAS  PubMed  Google Scholar 

  56. Houzelstein, D. et al. The homeobox gene Msx1 is expressed in a subset of somites, and in muscle progenitor cells migrating into the forelimb. Development 126, 2689–2701 (1999).

    Article  CAS  PubMed  Google Scholar 

  57. Bendall, A. J., Ding, J., Hu, G., Shen, M. M. & Abate-Shen, C. Msx1 antagonizes the myogenic activity of Pax3 in migrating limb muscle precursors. Development 126, 4965–4976 (1999).

    Article  CAS  PubMed  Google Scholar 

  58. Woloshin, P. et al. MSX1 inhibits myoD expression in fibroblast × 10T1/2 cell hybrids. Cell 82, 611–620 (1995).

    Article  CAS  PubMed  Google Scholar 

  59. Odelberg, S. J., Kollhoff, A. & Keating, M. T. Dedifferentiation of mammalian myotubes induced by msx1. Cell 103, 1099–1109 (2000).

    Article  CAS  PubMed  Google Scholar 

  60. Williams, B. A. & Ordahl, C. P. Pax-3 expression in segmental mesoderm marks early stages in myogenic cell specification. Development 120, 785–796 (1994).

    Article  CAS  PubMed  Google Scholar 

  61. Bober, E., Franz, T., Arnold, H. H., Gruss, P. & Tremblay, P. Pax-3 is required for the development of limb muscles: a possible role for the migration of dermomyotomal muscle progenitor cells. Development 120, 603–612 (1994).

    Article  CAS  PubMed  Google Scholar 

  62. Daston, G., Lamar, E., Olivier, M. & Goulding, M. Pax-3 is necessary for migration but not differentiation of limb muscle precursors in the mouse. Development 122, 1017–1027 (1996).

    Article  CAS  PubMed  Google Scholar 

  63. Tremblay, P. et al. A crucial role for Pax3 in the development of the hypaxial musculature and the long-range migration of muscle precursors. Dev. Biol. 203, 49–61 (1998).

    Article  CAS  PubMed  Google Scholar 

  64. Seale, P. et al. Pax7 is required for the specification of myogenic satellite cells. Cell 102, 777–786 (2000). This work on Pax7 -deficient muscles shows that Pax7 is required for the development of the satellite-cell lineage, but not for embryonic and fetal muscle lineages.

    Article  CAS  PubMed  Google Scholar 

  65. Borycki, A. G., Li, J., Jin, F., Emerson, C. P. & Epstein, J. A. Pax3 functions in cell survival and in pax7 regulation. Development 126, 1665–1674 (1999).

    Article  CAS  PubMed  Google Scholar 

  66. Tajbakhsh, S., Rocancourt, D., Cossu, G. & Buckingham, M. Redefining the genetic hierarchies controlling skeletal myogenesis: Pax-3 and Myf-5 act upstream of MyoD. Cell 89, 127–138 (1997). This important article defines a hierarchical genetic relationship whereby Pax3 and Myf5 function upstream of MyoD for embryonic body-muscle development.

    Article  CAS  PubMed  Google Scholar 

  67. Maroto, M. et al. Ectopic Pax-3 activates MyoD and Myf-5 expression in embryonic mesoderm and neural tissue. Cell 89, 139–48 (1997).

    Article  CAS  PubMed  Google Scholar 

  68. Ridgeway, A. G. & Skerjanc, I. S. Pax3 is essential for skeletal myogenesis and the expression of Six1 and Eya2. J. Biol. Chem. 276, 19033–19039 (2001).

    Article  CAS  PubMed  Google Scholar 

  69. Magnaghi, P., Roberts, C., Lorain, S., Lipinski, M. & Scambler, P. J. HIRA, a mammalian homologue of Saccharomyces cerevisiae transcriptional co-repressors, interacts with Pax3. Nature Genet. 20, 74–77 (1998).

    Article  CAS  PubMed  Google Scholar 

  70. Lagutina, I., Conway, S. J., Sublett, J. & Grosveld, G. C. Pax3-FKHR knock-in mice show developmental aberrations but do not develop tumors. Mol. Cell. Biol. 22, 7204–7216 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Khan, J. et al. cDNA microarrays detect activation of a myogenic transcription program by the PAX3-FKHR fusion oncogene. Proc. Natl Acad. Sci. USA 96, 13264–13269 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ridgeway, A. G., Petropoulos, H., Wilton, S. & Skerjanc, I. S. Wnt signaling regulates the function of MyoD and myogenin. J. Biol. Chem. 275, 32398–32405 (2000).

    Article  CAS  PubMed  Google Scholar 

  73. Petropoulos, H. & Skerjanc, I. S. β-catenin is essential and sufficient for skeletal myogenesis in p19 cells. J. Biol. Chem. 277, 15393–15399 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. Spitz, F. et al. Expression of myogenin during embryogenesis is controlled by Six/sine oculis homeoproteins through a conserved MEF3 binding site. Proc. Natl Acad. Sci. USA 95, 14220–14225 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Heanue, T. A. et al. Synergistic regulation of vertebrate muscle development by Dach2, Eya2, and Six1, homologs of genes required for Drosophila eye formation. Genes Dev. 13, 3231–3243 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kardon, G., Heanue, T. A. & Tabin, C. J. Pax3 and Dach2 positive regulation in the developing somite. Dev. Dyn. 224, 350–355 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Laclef, C. et al. Altered myogenesis in Six1-deficient mice. Development 130, 2239–2252 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Bladt, F., Riethmacher, D., Isenmann, S., Aguzzi, A. & Birchmeier, C. Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud. Nature 376, 768–771 (1995).

    Article  CAS  PubMed  Google Scholar 

  79. Epstein, J. A., Shapiro, D. N., Cheng, J., Lam, P. Y. & Maas, R. L. Pax3 modulates expression of the c-Met receptor during limb muscle development. Proc. Natl Acad. Sci. USA 93, 4213–4218 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Mennerich, D., Schafer, K. & Braun, T. Pax-3 is necessary but not sufficient for lbx1 expression in myogenic precursor cells of the limb. Mech. Dev. 73, 147–158 (1998).

    Article  CAS  PubMed  Google Scholar 

  81. Mennerich, D. & Braun, T. Activation of myogenesis by the homeobox gene Lbx1 requires cell proliferation. EMBO J. 20, 7174–7183 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Brohmann, H., Jagla, K. & Birchmeier, C. The role of Lbx1 in migration of muscle precursor cells. Development 127, 437–445 (2000).

    Article  CAS  PubMed  Google Scholar 

  83. Gross, M. K. et al. Lbx1 is required for muscle precursor migration along a lateral pathway into the limb. Development 127, 413–424 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Schafer, K. & Braun, T. Early specification of limb muscle precursor cells by the homeobox gene Lbx1h. Nature Genet. 23, 213–216 (1999).

    Article  CAS  PubMed  Google Scholar 

  85. Schultz, E. Satellite cell proliferative compartments in growing skeletal muscles. Dev. Biol. 175, 84–94 (1996).

    Article  CAS  PubMed  Google Scholar 

  86. Bischoff, R. in Myology (eds Engel, A. G. & Franzini-Armstrong, C.) 97–118 (McGraw Hill, New York, 1994).

    Google Scholar 

  87. Hawke, T. J. & Garry, D. J. Myogenic satellite cells: physiology to molecular biology. J. Appl. Physiol. 91, 534–551 (2001).

    Article  CAS  PubMed  Google Scholar 

  88. Seale, P. & Rudnicki, M. A. in Stem Cells: A Cellular Fountain of Youth (eds Mattson, M. P. & Van Zant, G.) 177–200 (Elsevier, New York, 2002).

    Book  Google Scholar 

  89. Armand, O., Boutineau, A. M., Mauger, A., Pautou, M. P. & Kieny, M. Origin of satellite cells in avian skeletal muscles. Arch. Anat. Microsc. Morphol. Exp. 72, 163–181 (1983).

    CAS  PubMed  Google Scholar 

  90. De Angelis, L. et al. Skeletal myogenic progenitors originating from embryonic dorsal aorta coexpress endothelial and myogenic markers and contribute to postnatal muscle growth and regeneration. J. Cell. Biol. 147, 869–878 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Pardanaud, L. & Dieterlen-Lievre, F. Ontogeny of the endothelial system in the avian model. Adv. Exp. Med. Biol. 476, 67–78 (2000).

    Article  CAS  PubMed  Google Scholar 

  92. Beauchamp, J. R. et al. Expression of CD34 and Myf5 defines the majority of quiescent adult skeletal muscle satellite cells. J. Cell. Biol. 151, 1221–1234 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Smith, C. K., Janney, M. J. & Allen, R. E. Temporal expression of myogenic regulatory genes during activation, proliferation and differentiation of rat skeletal muscle satellite cells. J. Cell. Physiol. 159, 379–385 (1994).

    Article  CAS  PubMed  Google Scholar 

  94. Cornelison, D. D. & Wold, B. J. Single-cell analysis of regulatory gene expression in quiescent and activated mouse skeletal muscle satellite cells. Dev. Biol. 191, 270–283 (1997).

    Article  CAS  PubMed  Google Scholar 

  95. Seale, P. & Rudnicki, M. A. A new look at the origin, function, and “stem-cell” status of muscle satellite cells. Dev. Biol. 218, 115–124 (2000).

    Article  CAS  PubMed  Google Scholar 

  96. Megeney, L. A., Kablar, B., Garrett, K., Anderson, J. E. & Rudnicki, M. A. MyoD is required for myogenic stem cell function in adult skeletal muscle. Genes Dev. 10, 1173–1183 (1996).

    Article  CAS  PubMed  Google Scholar 

  97. Sabourin, L. A., Girgis-Gabardo, A., Seale, P., Asakura, A. & Rudnicki, M. A. Reduced differentiation potential of primary MyoD−/− myogenic cells derived from adult skeletal muscle. J. Cell. Biol. 144, 631–643 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Yablonka-Reuveni, Z. et al. The transition from proliferation to differentiation is delayed in satellite cells from mice lacking MyoD. Dev. Biol. 210, 440–455 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Cornelison, D. D., Olwin, B. B., Rudnicki, M. A. & Wold, B. J. MyoD(−/−) satellite cells in single-fiber culture are differentiation defective and MRF4 deficient. Dev. Biol. 224, 122–137 (2000).

    Article  CAS  PubMed  Google Scholar 

  100. Kaul, A., Koster, M., Neuhaus, H. & Braun, T. Myf-5 revisited: loss of early myotome formation does not lead to a rib phenotype in homozygous Myf-5 mutant mice. Cell 102, 17–19 (2000).

    Article  CAS  PubMed  Google Scholar 

  101. Zhao, P. et al. Slug is a novel downstream target of MyoD. Temporal profiling in muscle regeneration. J. Biol. Chem. 277, 30091–30101 (2002).

    Article  CAS  PubMed  Google Scholar 

  102. Montarras, D., Lindon, C., Pinset, C. & Domeyne, P. Cultured myf5 null and myoD null muscle precursor cells display distinct growth defects. Biol. Cell. 92, 565–572 (2000).

    Article  CAS  PubMed  Google Scholar 

  103. Bergstrom, D. A. et al. Promoter-specific regulation of MyoD binding and signal transduction cooperate to pattern gene expression. Mol. Cell. 9, 587–600 (2002). This paper examines MyoD-specific gene expression and shows how MyoD regulates the expression of groups of genes in a manner that is dependent on promoter context.

    Article  CAS  PubMed  Google Scholar 

  104. Asakura, A., Komaki, M. & Rudnicki, M. Muscle satellite cells are multipotential stem cells that exhibit myogenic, osteogenic, and adipogenic differentiation. Differentiation 68, 245–253 (2001).

    Article  CAS  PubMed  Google Scholar 

  105. Wada, M. R., Inagawa-Ogashiwa, M., Shimizu, S., Yasumoto, S. & Hashimoto, N. Generation of different fates from multipotent muscle stem cells. Development 129, 2987–2995 (2002).

    Article  CAS  PubMed  Google Scholar 

  106. Conboy, I. M. & Rando, T. A. The regulation of Notch signaling controls satellite cell activation and cell fate determination in postnatal myogenesis. Dev. Cell 3, 397–409 (2002).

    Article  CAS  PubMed  Google Scholar 

  107. Shen, Q., Zhong, W., Jan, Y. N. & Temple, S. Asymmetric Numb distribution is critical for asymmetric cell division of mouse cerebral cortical stem cells and neuroblasts. Development 129, 4843–4853 (2002).

    Article  CAS  PubMed  Google Scholar 

  108. Rath, P. et al. Inscuteable-independent apicobasally oriented asymmetric divisions in the Drosophila embryonic CNS. EMBO Rep. 3, 660–665 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Dooley, C. M., James, J., Jane McGlade, C. & Ahmad, I. Involvement of numb in vertebrate retinal development: evidence for multiple roles of numb in neural differentiation and maturation. J. Neurobiol. 54, 313–325 (2003).

    Article  CAS  PubMed  Google Scholar 

  110. Buckingham, M. et al. The formation of skeletal muscle: from somite to limb. J. Anat. 202, 59–68 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Tatsumi, R., Anderson, J. E., Nevoret, C. J., Halevy, O. & Allen, R. E. HGF/SF is present in normal adult skeletal muscle and is capable of activating satellite cells. Dev. Biol. 194, 114–128 (1998).

    Article  CAS  PubMed  Google Scholar 

  112. Allen, R. E., Sheehan, S. M., Taylor, R. G., Kendall, T. L. & Rice, G. M. Hepatocyte growth factor activates quiescent skeletal muscle satellite cells in vitro. J. Cell. Physiol. 165, 307–312 (1995).

    Article  CAS  PubMed  Google Scholar 

  113. Anastasi, S. et al. A natural hepatocyte growth factor/scatter factor autocrine loop in myoblast cells and the effect of the constitutive Met kinase activation on myogenic differentiation. J. Cell. Biol. 137, 1057–1068 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Rudnicki, M. A. et al. MyoD or Myf-5 is required for the formation of skeletal muscle. Cell 75, 1351–1359 (1993).

    Article  CAS  PubMed  Google Scholar 

  115. Partridge, T. The current status of myoblast transfer. Neurol. Sci. 21, S939–S942 (2000).

    Article  CAS  PubMed  Google Scholar 

  116. Bittner, R. E. et al. Recruitment of bone-marrow-derived cells by skeletal and cardiac muscle in adult dystrophic mdx mice. Anat. Embryol. 199, 391–396 (1999).

    Article  CAS  Google Scholar 

  117. Gussoni, E. et al. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature 401, 390–394 (1999).

    CAS  PubMed  Google Scholar 

  118. Wakeford, S., Watt, D. J. & Partridge, T. A. X-irradiation improves mdx mouse muscle as a model of myofiber loss in DMD. Muscle Nerve 14, 42–50 (1991).

    Article  CAS  PubMed  Google Scholar 

  119. Pagel, C. N. & Partridge, T. A. Covert persistence of mdx mouse myopathy is revealed by acute and chronic effects of irradiation. J. Neurol. Sci. 164, 103–116 (1999).

    Article  CAS  PubMed  Google Scholar 

  120. Goodell, M. A., Brose, K., Paradis, G., Conner, A. S. & Mulligan, R. C. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J. Exp. Med. 183, 1797–1806 (1996).

    Article  CAS  PubMed  Google Scholar 

  121. Goodell, M. A. et al. Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species. Nature Med. 3, 1337–1345 (1997).

    Article  CAS  PubMed  Google Scholar 

  122. Asakura, A., Seale, P., Girgis-Gabardo, A. & Rudnicki, M. A. Myogenic specification of side population cells in skeletal muscle. J. Cell. Biol. 159, 123–134 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Lee, J. Y. et al. Clonal isolation of muscle-derived cells capable of enhancing muscle regeneration and bone healing. J. Cell. Biol. 150, 1085–1100 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Torrente, Y. et al. Intraarterial injection of muscle-derived CD34(+)Sca-1(+) stem cells restores dystrophin in mdx mice. J. Cell. Biol. 152, 335–348 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Baylies, M. K. & Michelson, A. M. Invertebrate myogenesis: looking back to the future of muscle development. Curr. Opin. Genet. Dev. 11, 431–439 (2001).

    Article  CAS  PubMed  Google Scholar 

  126. Arbeitman, M. N. et al. Gene expression during the life cycle of Drosophila melanogaster. Science 297, 2270–2275 (2002).

    Article  CAS  PubMed  Google Scholar 

  127. Semsarian, C. et al. Skeletal muscle hypertrophy is mediated by a Ca2+-dependent calcineurin signalling pathway. Nature 400, 576–581 (1999).

    Article  CAS  PubMed  Google Scholar 

  128. Sakuma, K. et al. Calcineurin is a potent regulator for skeletal muscle regeneration by association with NFATc1 and GATA-2. Acta Neuropathol. 105, 271–280 (2003).

    Article  CAS  PubMed  Google Scholar 

  129. Musaro, A., McCullagh, K. J., Naya, F. J., Olson, E. N. & Rosenthal, N. IGF-1 induces skeletal myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATc1. Nature 400, 581–585 (1999).

    Article  CAS  PubMed  Google Scholar 

  130. Musaro, A. et al. Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nature Genet. 27, 195–200 (2001).

    Article  CAS  PubMed  Google Scholar 

  131. Friday, B. B. & Pavlath, G. K. A calcineurin- and NFAT-dependent pathway regulates Myf5 gene expression in skeletal muscle reserve cells. J. Cell. Sci. 114, 303–310 (2001).

    Article  CAS  PubMed  Google Scholar 

  132. Liu, D., Black, B. L. & Derynck, R. TGF-β inhibits muscle differentiation through functional repression of myogenic transcription factors by Smad3. Genes Dev. 15, 2950–2966 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Cornelison, D. D., Filla, M. S., Stanley, H. M., Rapraeger, A. C. & Olwin, B. B. Syndecan-3 and syndecan-4 specifically mark skeletal muscle satellite cells and are implicated in satellite cell maintenance and muscle regeneration. Dev. Biol. 239, 79–94 (2001).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank B. B. Olwin for generously providing anti-syndecan-4 antibody. P.S. is supported by a Doctoral Research Award from the Canadian Institutes of Health Research. M.A.R. holds the Canada Research Chair in Molecular Genetics and is a Howard Hughes Medical Institute International Scholar. This work was supported by grants to M.A.R. from the Muscular Dystrophy Association, the National Institutes of Health, the Canadian Institutes of Health Research, the Howard Hughes Medical Institute and the Canada Research Chair Program.

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Author notes

  1. Maura H. Parker and Patrick Seale: These authors contributed equally to this paper.

Authors and Affiliations

  1. Ottawa Health Research Institute, Molecular Medicine Program, 501 Smyth Road, Ottawa, K1H 8L6, Ontario, Canada

    Maura H. Parker, Patrick Seale & Michael A. Rudnicki

  2. Faculty of Health Sciences, McMaster University, Hamilton, L8S 4K1, Ontario, Canada

    Maura H. Parker

  3. Department of Biology, McMaster University, Hamilton, L8S 4K1, Ontario, Canada

    Patrick Seale

Authors
  1. Maura H. Parker
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Correspondence to Michael A. Rudnicki.

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DATABASES

Entrez

Bmp-2

Bmp-4

Bmp-7

Dach2

Eya2

Hgf

Lbx1

Myf5

Myf6

MyoD

myogenin

Numb

Pax3

Pax7

Shh

Six1

Wnt-4

Wnt-6

Wnt-7a

FlyBase

Mef2

twi

LocusLink

Dach2

Des

Dmd

Eya2

Hgf

Lbx1h

Meox1

Myf5

Myf6

Myog

Nog

Numb

Pax3

Pax7

Sdc4

Six1

Snai2

twi

Glossary

MYOGENIC

Cells that are committed to become muscle.

SATELLITE CELLS

Quiescent cells that are located between the basal lamina and the plasmalemma of the muscle fibre, which are the main contributors to postnatal muscle growth.

COMMITMENT

The restriction of cells to a particular developmental fate before differentiation.

DETERMINATION

The process of irreversible specification, whereby a cell becomes able to differentiate autonomously, even if placed in another part of the embryo.

SPECIFICATION

The process by which cells acquire a fate.

PARAXIAL MESODERM

The embryonic tissue layer that forms on either side of the notochord and gives rise to the somites, which develop into the muscles, bones and cartilage.

LATERAL-PLATE MESODERM

Part of the mesoderm that forms several different tissues and organs, and is the source of various regulatory signals, such as the bone morphogenic proteins.

FATE

What a cell and its progeny will give rise to in a later stage of development; cells become progressively more restricted in their fate as development progresses.

MYOTUBES

Multinucleated cells that are formed when proliferating myoblasts exit the cell cycle, differentiate and fuse.

MYOFIBRES

Muscle fibres that are formed by the maturation of myotubes, which can be classed as slow, intermediate/fast or fast.

TERMINAL DIFFERENTIATION

The formation of a specialized cell type through a process that is not normally reversible.

OSTEOGENIC

Cells that are specified to become bone.

ADIPOGENIC

Cells that are specified to become adipose or fat tissue.

CHONDROGENIC

Cells that are specified to become cartilage.

SOMITIC ANGIOBLASTS

Endothelial progenitors that arise in the somite.

MULTIPOTENTIAL STEM CELL

A cell that has an intrinsic capacity to give rise to more than one differentiated cell lineage.

PROGENITOR COMPARTMENT

A population of cells that can give rise to more specialized cell types during development and differentiation.

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Parker, M., Seale, P. & Rudnicki, M. Looking back to the embryo: defining transcriptional networks in adult myogenesis. Nat Rev Genet 4, 497–507 (2003). https://doi.org/10.1038/nrg1109

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