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
- Frédéric Relaix1,
- Mariarosa Polimeni2,
- Didier Rocancourt1,
- Carola Ponzetto3,
- Beat W. Schäfer4, and
- Margaret Buckingham1,5
- 1 CNRS URA 2375, Department of Developmental Biology, Pasteur Institute, 75724 Paris Cedex 15, France
- 2 Department of Experimental Medicine, Section of Anatomy, University of Pavia, 27100 Pavia, Italy
- 3 Department of Anatomy, Pharmacology and Forensic Medicine, University of Turin, 10126 Turin, Italy
- 4 Division of Clinical Chemistry and Biochemistry, Department of Pediatrics, University of Zurich, CH-8032 Zurich, Switzerland
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.
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Footnotes
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Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.281203.
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↵5 Corresponding author. E-MAIL margab{at}pasteur.fr; FAX 33-1-40-61-34-52.
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- Accepted October 22, 2003.
- Received July 30, 2003.
- Cold Spring Harbor Laboratory Press