Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Early specification of limb muscle precursor cells by the homeobox gene Lbx1h

Nature Genetics volume 23, pages 213–216 (1999)Cite this article

Abstract

During vertebrate embryogenesis, myogenic precursor cells of limb muscles delaminate from the ventro-lateral edge of the somitic dermomyotome and migrate to the limb buds, where they congregate into dorsal and ventral muscle masses1,2. It has been proposed that the surrounding connective tissue controls muscle pattern formation in limbs3,4,5. Regulatory molecules such as receptor tyrosine kinases like c-Met ( ref. 6) and those encoded by homeobox-containing genes, including c-Met (ref. 6), Tbx1 ( ref. 7), Mox2 (ref. 8), Six1 and Six2 (ref. 9), Pitx2, Pax3 (refs 10,11) and Lbx1h (refs 12,13), are expressed in migrating limb precursor cells. The role of these genes in the patterning of limb muscles is unknown, although mutation of Pax3 or Met causes disruption of limb muscle development at an initial step, disturbing the epithelial-to-mesenchymal transition of the somitic epithelium6,10,11. No limb muscle cells form in these mutants, and the early loss of myogenic precursor cells prevented an analysis of later functions of these genes during limb muscle development14. Based on quail-chick chimaera studies3,15, it was assumed that a cell-autonomous contribution of myogenic cells to the formation of individual limb muscles is negligible, and that an instructive role of limb mesenchyme is critical in this process. Here we show that Lbx1h determines migratory routes of muscle precursor cells in a cell-autonomous manner, thereby leading to the formation of distinct limb muscle patterns. Inactivation of Lbx1h, which is specifically expressed in migrating muscle precursor cells12,13, led to a lack of extensor muscles in forelimbs and an absence of muscles in hindlimbs. The defect was caused by the failure of all muscle precursor cells of hindlimbs and of precursor cells of extensor muscles of forelimbs to migrate to their corresponding muscle anlagen. Our results demonstrate that Lbx1h is a key regulator of muscle precursor cell migration and is required for the acquisition of dorsal identities of forelimb muscles.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Targeted mutagenesis of the Lbx1h locus.
Figure 2: Absence of extensor muscles in forelimbs of Lbx1h–/– neonates.
Figure 3: Aberrant migration of limb muscle precursor cells lacking Lbx1h .
Figure 4: Altered gene expression of muscle precursor cell markers in forelimbs of Lbx1h–/– embryos.

Similar content being viewed by others

References

  1. Christ, B., Jacob, H.J. & Jacob, M. Experimental analysis of the origin of the wing musculature in avian embryos. Anat. Embryol. (Berl) 150, 171–186 (1977).

    Article  CAS  Google Scholar 

  2. Martin, P. Tissue patterning in the developing mouse limb. Int. J. Dev. Biol. 34, 323–336 ( 1990).

    CAS  PubMed  Google Scholar 

  3. Chevallier, A. & Kieny, M. On the role of the connective tissue in the patterning of the chick limb musculature. Wilhelm Roux's Arch. Dev. Biol. 191, 277–280 (1982).

    Article  Google Scholar 

  4. Mauger, A., Kieny, M., Hedayat, I. & Goetinck, P.F. Tissue interactions in the organization and maintenance of the muscle pattern in the chick limb. J. Embryol. Exp. Morphol. 76, 199– 215 (1983).

    CAS  PubMed  Google Scholar 

  5. Brand-Saberi, B., Wilting, J., Ebensperger, C. & Christ, B. The formation of somite compartments in the avian embryo. Int. J. Dev. Biol. 40, 411–420 (1996).

    CAS  PubMed  Google Scholar 

  6. 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  Google Scholar 

  7. Isaac, A. et al. Tbx genes and limb identity in chick embryo development. Development 125, 1867–1875 (1998).

    CAS  PubMed  Google Scholar 

  8. Candia, A.F. & Wright, C.V. Differential localization of Mox-1 and Mox-2 proteins indicates distinct roles during development. Int. J. Dev. Biol. 40, 1179–1184 (1996).

    CAS  PubMed  Google Scholar 

  9. Oliver, G. et al. Homeobox genes and connective tissue patterning. Development 121, 693–705 (1995).

    CAS  PubMed  Google Scholar 

  10. 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).

    CAS  PubMed  Google Scholar 

  11. 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).

    CAS  PubMed  Google Scholar 

  12. Jagla, K. et al. Mouse Lbx1 and human LBX1 define a novel mammalian homeobox gene family related to the Drosophila lady bird genes. Mech. Dev. 53, 345–356 ( 1995).

    Article  CAS  Google Scholar 

  13. 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  Google Scholar 

  14. 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).

    CAS  PubMed  Google Scholar 

  15. Butler, J., Cosmos, E. & Cauwenbergs, P.C. Positional signals: evidence for a possible role in muscle fibre-type patterning of the embryonic avian limb. Development 102, 763–772 ( 1988).

    Google Scholar 

  16. 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  Google Scholar 

  17. Sassoon, D. et al. Expression of two myogenic regulatory factors myogenin and MyoD1 during mouse embryogenesis. Nature 341, 303–307 (1989).

    Article  CAS  Google Scholar 

  18. Braun, T., Rudnicki, M.A., Arnold, H.-H. & Jaenisch, R. Targeted inactivation of the muscle regulatory gene myf-5 results in abnormal rib development and perinatal death. Cell 71, 369–382 (1992).

    Article  CAS  Google Scholar 

  19. Bancroft, J.D. & Stevens, A. Theory and Practice of Histological Techniques (Churchill Livingston, Edinburgh, 1990).

    Google Scholar 

  20. Floss, T., Arnold, H.-H. & Braun, T. A role for FGF-6 in skeletal muscle regeneration. Genes Dev. 11, 2040–2052 (1997).

    Article  CAS  Google Scholar 

  21. Zweigerdt, R., Braun, T. & Arnold, H.-H. Faithful expression of the Myf-5 gene during mouse myogenesis requires distant control regions: a transgene approach using yeast artificial chromosomes. Dev. Biol. 192, 172– 180 (1997).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank E. Bober and R. Schnabel for reading the manuscript; R. Jaenisch for the genomic phage library; R. Faessler for pWH9; and H.-H. Arnold for support and encouragement during the initial phase of the project. This work was supported by the SFB 271: Molekulare Mechanismen Morphoregulatorischer Prozesse DFG Grant Br1413/4–1 to T.B., Fonds der Chemischen Industrie and the Boehringer Ingelheim Fonds für Medizinische Grundlagenforschung.

Author information

Authors and Affiliations

  1. Institute of Physiological Chemistry, Martin-Luther-University Halle,, Hollystr. 1, Halle, 06097, Germany

    Konstanze Schäfer & Thomas Braun

Authors
  1. Konstanze Schäfer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas Braun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas Braun.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schäfer, K., Braun, T. Early specification of limb muscle precursor cells by the homeobox gene Lbx1h. Nat Genet 23, 213–216 (1999). https://doi.org/10.1038/13843

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/13843

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing