title: The transcriptional activator PAX3-FKHR rescues the defects of Pax3 mutant mice but induces a myogenic gain-of-function phenotype with ligand-independent activation of Met signaling in vivo.
abstract: Pax3 is a key transcription factor implicated in development and human disease. To dissect the role of Pax3 in myogenesis and establish whether it is a repressor or activator, we generated loss- and gain-of-function alleles by targeting an nLacZ reporter and a sequence encoding the oncogenic fusion protein PAX3-FKHR into the Pax3 locus. Rescue of the Pax3 mutant phenotypes by PAX3-FKHR suggests that Pax3 acts as a transcriptional activator during embryogenesis. This is confirmed by a Pax reporter mouse. However, mice expressing PAX3-FKHR display developmental defects, including ectopic delamination and inappropriate migration of muscle precursor cells. These events result from overexpression of c-met, leading to constitutive activation of Met signaling, despite the absence of the ligand SF/HGF. Haploinsufficiency of c-met rescues this phenotype, confirming the direct genetic link with Pax3. The gain-of-function phenotype is also characterized by overactivation of MyoD. The consequences of PAX3-FKHR myogenic activity in the limbs and cervical and thoracic regions point to differential regulation of muscle growth and patterning. This gain-of-function allele provides a new approach to the molecular and cellular analysis of the role of Pax3 and of its target genes in vivo.
authors.affiliation: CNRS URA 2375, Department of Developmental Biology, Pasteur Institute, 75724 Paris Cedex 15, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Relaix
authors.forename: Mariarosa
authors.initials: M
authors.lastname: Polimeni
authors.forename: Didier
authors.initials: D
authors.lastname: Rocancourt
authors.forename: Carola
authors.initials: C
authors.lastname: Ponzetto
authors.forename: Beat W
authors.initials: BW
authors.lastname: Schäfer
authors.forename: Margaret
authors.initials: M
authors.lastname: Buckingham
mesh_terms: D000483:Alleles; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D007150:Immunohistochemistry; D051379:Mice; D008817:Mice, Mutant Strains; D009124:Muscle Proteins / Q000502:physiology; D017570:MyoD Protein / Q000502:physiology; D051787:Myogenic Regulatory Factor 5; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D010641:Phenotype; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D009124:Muscle Proteins; C497418:Myf5 protein, mouse; D017570:MyoD Protein; D051787:Myogenic Regulatory Factor 5; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D015534:Trans-Activators; D014157:Transcription Factors; C068686:Pax3 protein, mouse; D019859:Proto-Oncogene Proteins c-met