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Developmental Biology Tutorial
Initiation of skeletal muscle development
What regulates the MRF genes?
Transplantation experiments with chick embryos have shown that the somites
are induced by the neural tube/notochord complex to form muscle (Rong et
al., 1992; Buffinger and Stockdale, 1994). Recent evidence (Yun and
Wold, 1966) has indicated that dermomyotome-specific gene expression is
induced by Wnts produced by the dorsal neural tube and surface ectoderm,
whereas sonic hedgehog (Shh) from the notochord and ventral floorplate of
the neural tube induces sclerotome-specific gene expression. The activation
of the myogenic pathway in the myotome is a consequence of combinatorial
effects of the Wnts and Shh. Yet another signal from the lateral mesoderm
(possibly bone morphogenetic protein; BMP) inhibits myogenesis. These signals
diffuse from their respective origins. The overlapping signals produce discrete
concentrations of the secreted factors in the somite and specify cellular
identities in the different somite domains (Rawls and Olson, 1997).
How do these signals cause the expression of the MRF genes, which promote
myogenesis? The paired-type homeobox gene Pax-3 has now been shown
to be a key trigger of the myogenic program by virtue of its activation
of MyoD expression (Rawls and Olson, 1997). Pax-3 (and a related
protein Pax-7) is expressed in the paraxial mesoderm before the somites
form. When the somites become epithelial, Pax-3 and Pax-7 are expressed
in the dorsal halves of the somites. Later, Pax-3 becomes restricted to
the ventrolateral domain, whereas Pax-7 is expressed in the dorsomedial
domain. Pax-3 is also expressed in the myogenic precursors that migrate
from the dermomyotome into the limb buds (Goulding et al., 1991;
Jostes et al., 1991).
The splotch mutant in the mouse lacks a functional Pax-3 gene.
Consequently, this mutant provides a means to establish whether there is
any functional relationship between Pax-3 and myogenesis. These mice lack
limb muscles, but muscles of the back and body wall are unaffected (Bober
et al., 1994). (Recall that the limb myogenic precursors are derived
from the ventrolateral edge of the dermomyotome and that this pathway is
initiated by expression of MyoD.)
More specific evidence on the role of Pax-3 in myogenesis has come from
examinations of mice that were deficient for both Pax-3 and Myf-5
(Tajbakhsh et al., 1997). These mice developed virtually no muscle
in the trunk region and did not express MyoD in this region. It has previously been shown that Myf-5 mutant
mice will express MyoD and form muscle in this region. Therefore, this new
result suggests that there are two pathways for formation of muscle in the
trunk: a Pax-3-dependent pathway and a Pax-3-independent pathway that is
regulated by Myf-5.
So, is Pax-3 sufficient to initiate the myogenic program? Maroto et al.
(1997) have shown that viral-mediated ectopic expression of Pax-3
in chick embryoic tissue activated MyoD expression and myogenesis.
The experiments of Tajbakhsh et al. (1997) and Maroto et al.
(1997) have shown that the "master regulator" MyoD is itself a
component of a continuum of regulatory events. The ultimate aim of contemporary
developmental biology is to describe all of the components of that continuum
and understand how a fertilized egg can produce muscle (and all other differentiated
cell types) in the right place and at the right time.
- Review the identities, origins and proposed functions of the various
signals that promote somite regionalization.
- Integrate what you have learned here with your previous knowledge about
the roles of the MRF genes. For example, compare the results of the Pax-3/Myf-5
knockouts to those of the MyoD/Myf-5
- What is the evidence that Pax-3 is sufficient to initiate myogenesis?
Bober, E., Franz, T., Arnold, H.H., Gruss, P. and Tremblay, P. 1994.
Pax-3 is required for the development of limb muscles: a possible role for
the migration of dermomyotomal muscle progenitor cells. Development 120:
Buffinger, N. and F.E. Stockdale. 1994. Myogenic specification in somites:
induction by axial structures. Development 120: 1443-1452.
Goulding, M.D., Chalepakis, G., Deutsch, U., Erselius, J.R. and Gruss, P.
1991. Pax-3, a novel murine DNA binding protein expressed during early myogenesis.
EMBO J. 10: 1135-1147.
Jostes, B., Walther, C. and Gruss, P. 1991. The murine paired box gene,
Pax 7, is expressed specifically during the development of the nervous and
muscular system. Mech. Dev. 33: 27-38.
Maroto, M., Reshef, R., Münsterberg, A.E., Koester, S., Goulding, M.
and Lassar. A.B. 1997. Ectopic Pax-3 activates MyoD and Myf-5
expression in embryonic mesoderm and neural tissue. Cell 89: 139-148.
Rawls, A. and Olson, E.N. 1997. MyoD meets its maker. Cell 89: 5-8.
Rong, P.M., M.-A. Teillet, C. Ziller et al. 1992. The neural tube/notochord
complex is necessary for vertebral but not limb and body wall striated muscle
differentiation. Development 115: 657-672.
Tajbakhsh, S., Rocancourt, D., Cossu, G. and Buckingham, M. 1997. Redefining
the genetic hierarchies controlling skeletal myogenesis: Pax-3 and
Myf-5 act upstream of MyoD. Cell 89: 127-138.
Yun, K. and Wold, B. 1996. Skeletal muscle determination and differentiation:
story of a core regulatory network and its context. Curr. Opin. Cell Biol.