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

Genes Dev. 2003 Dec 1;17(23):2950-65. doi: 10.1101/gad.281203.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Immunohistochemistry
  • Mice
  • Mice, Mutant Strains
  • Muscle Proteins / physiology
  • MyoD Protein / physiology
  • Myogenic Regulatory Factor 5
  • PAX3 Transcription Factor
  • Paired Box Transcription Factors
  • Phenotype
  • Proto-Oncogene Proteins c-met / physiology*
  • Signal Transduction*
  • Trans-Activators*
  • Transcription Factors / physiology*

Substances

  • DNA-Binding Proteins
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • Muscle Proteins
  • Myf5 protein, mouse
  • MyoD Protein
  • Myogenic Regulatory Factor 5
  • PAX3 Transcription Factor
  • PAX3 protein, human
  • Paired Box Transcription Factors
  • Trans-Activators
  • Transcription Factors
  • Pax3 protein, mouse
  • Proto-Oncogene Proteins c-met

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