Divergent functions of murine Pax3 and Pax7 in limb muscle development.
Pax genes encode evolutionarily conserved transcription factors that play critical roles in development. Pax3 and Pax7 constitute one of the four Pax subfamilies. Despite partially overlapping expression domains, mouse mutations for Pax3 and Pax7 have very different consequences. To investigate the mechanism of these contrasting phenotypes, we replaced Pax3 by Pax7 by using gene targeting in the mouse. Pax7 can substitute for Pax3 function in dorsal neural tube, neural crest cell, and somite development, but not in the formation of muscles involving long-range migration of muscle progenitor cells. In limbs in which Pax3 is replaced by Pax7, the severity of the muscle phenotype increases as the number of Pax7 replacement alleles is reduced, with the forelimb more affected than the hindlimb. We show that this hypomorphic activity of Pax7 is due to defects in delamination, migration, and proliferation of muscle precursor cells with inefficient activation of c-met in the hypaxial domain of the somite. Despite this, overall muscle patterning is retained. We conclude that functions already prefigured by the single Pax3/7 gene present before vertebrate radiation are fulfilled by Pax7 as well as Pax3, whereas the role of Pax3 in appendicular muscle formation has diverged, reflecting the more recent origin of this mode of myogenesis.
Relaix
Frédéric
F
Centre National de la Recherche Scientifique (CNRS) URA 2578, Department of Developmental Biology, Pasteur Institute, 75724 Paris Cedex 15, France.
Rocancourt
Didier
D
Mansouri
Ahmed
A
Buckingham
Margaret
M
D000818:Animals; D005075:Biological Evolution; D019521:Body Patterning; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005121:Extremities / Q000196:embryology; D015870:Gene Expression; D018390:Gene Targeting; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D024510:Muscle Development / Q000235:genetics / Q000502:physiology*; D018482:Muscle, Skeletal / Q000196:embryology*; D009432:Neural Crest / Q000196:embryology; D000072041:PAX3 Transcription Factor; D051763:PAX7 Transcription Factor; D051761:Paired Box Transcription Factors; D010641:Phenotype; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D019170:Somites / Q000166:cytology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D000072041:PAX3 Transcription Factor; D051763:PAX7 Transcription Factor; D051761:Paired Box Transcription Factors; C497322:Pax7 protein, mouse; D014157:Transcription Factors; C068686:Pax3 protein, mouse; D019859:Proto-Oncogene Proteins c-met