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
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Relaix, F
Polimeni, M
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机构:Inst Pasteur, CNRS, URA 2375, Dept Dev Biol, F-75724 Paris 15, France
Polimeni, M
Rocancourt, D
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机构:Inst Pasteur, CNRS, URA 2375, Dept Dev Biol, F-75724 Paris 15, France
Rocancourt, D
Ponzetto, C
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机构:Inst Pasteur, CNRS, URA 2375, Dept Dev Biol, F-75724 Paris 15, France
Ponzetto, C
Schäfer, BW
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机构:Inst Pasteur, CNRS, URA 2375, Dept Dev Biol, F-75724 Paris 15, France
Schäfer, BW
Buckingham, M
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Inst Pasteur, CNRS, URA 2375, Dept Dev Biol, F-75724 Paris 15, FranceInst Pasteur, CNRS, URA 2375, Dept Dev Biol, F-75724 Paris 15, France
Buckingham, M
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[1] Inst Pasteur, CNRS, URA 2375, Dept Dev Biol, F-75724 Paris 15, France
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.
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Western Gen Hosp, MRC, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, ScotlandWestern Gen Hosp, MRC, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland
van Heyningen, V
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Williamson, KA
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Western Gen Hosp, MRC, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, ScotlandWestern Gen Hosp, MRC, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland
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Western Gen Hosp, MRC, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, ScotlandWestern Gen Hosp, MRC, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland
van Heyningen, V
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Williamson, KA
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Western Gen Hosp, MRC, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, ScotlandWestern Gen Hosp, MRC, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland