Redefining the Genetic Hierarchies Controlling Skeletal Myogenesis: Pax-3 and Myf-5 Act Upstream of MyoD

Abstract

We analyzed Pax-3 (splotch), Myf-5 (targeted with nlacZ), and splotch/Myf-5 homozygous mutant mice to investigate the roles that these genes play in programming skeletal myogenesis. In splotch and Myf-5 homozygous embryos, myogenic progenitor cell perturbations and early muscle defects are distinct. Remarkably, splotch/Myf-5 double homozygotes have a dramatic phenotype not seen in the individual mutants: body muscles are absent. MyoD does not rescue this double mutant phenotype since activation of this gene proves to be dependent on either Pax-3 or Myf-5. Therefore, Pax-3 and Myf-5 define two distinct myogenic pathways, and MyoD acts genetically downstream of these genes for myogenesis in the body. This genetic hierarchy does not appear to operate for head muscle formation.

Enhanced differentiation of human embryonic stem cells to mesenchymal progenitors by inhibition of TGF-β/activin/nodal signaling using SB-431542

“…(48) Additionally, the myoblasts showed an upregulation in Pax3, which is known to control the delamination and migration of somatic muscle progenitors to the limb bud (49) and, along with Myf5, is able to activate MyoD expression in the embryonic body. (50) Interestingly, several genes whose expression was reported previously to be directly or indirectly linked to Pax3 expression were also relatively highly expressed (Table 1), for example, Meox1. (51) In addition, the microarray analysis revealed also that Meox2 (5.5-fold) was upregulated; this has been shown to be an important regulator of limb myogenesis (52) and is able to physically interact with Pax3 in vitro.…”

Pax3 activation promotes the differentiation of mesenchymal stem cells toward the myogenic lineage

“…Accordingly, Splotch (Pax3-null) mice die by E14.5 due to a number of developmental defects including impaired neural tube closure, defects in neural crest-derived structures, failure of cells within the dermomyotome to delaminate, and therefore, absence of limb muscles [24,35,36]. This later defect is associated with a lack of migratory muscle progenitors, which prevents MyoD activation by Myf5 and Mrf4 [20,28,36,37]. Because of this important role in muscle specification, Pax3 is considered a master regulator of the embryonic myogenic program [24,27].…”

Pitx2c overexpression promotes cell proliferation and arrests differentiation in myoblasts

“…The stages of skeletal myogenesis are well defined (Buckingham et al, 2003). Pax3 expression marks the early step of myogenic cell specification and is required for proper cell delamination and migration from the dermomyotome (Tajbakhsh et al, 1997). Initiation of myogenic determination begins when precursor cells reach the limb and express the muscle regulatory factors (MRF) MyoD and Myf5 (Tajbakhsh and Buckingham, 1994).…”