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

被引:123
作者
Relaix, F
Polimeni, M
Rocancourt, D
Ponzetto, C
Schäfer, BW
Buckingham, M [1 ]
机构
[1] Inst Pasteur, CNRS, URA 2375, Dept Dev Biol, F-75724 Paris 15, France
[2] Univ Pavia, Sect Anat, Dept Expt Med, I-27100 Pavia, Italy
[3] Univ Turin, Dept Anat Pharmacol & Forens Med, I-10126 Turin, Italy
[4] Univ Zurich, Dept Pediat, Div Clin Chem & Biochem, CH-8032 Zurich, Switzerland
关键词
Pax3; Met; myogenesis; migration; mouse; embryo; rhabdomyosarcoma;
D O I
10.1101/gad.281203
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:2950 / 2965
页数:16
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