title: Pax3:Fkhr interferes with embryonic Pax3 and Pax7 function: implications for alveolar rhabdomyosarcoma cell of origin.
abstract: To investigate the role of the translocation-associated gene Pax3:Fkhr in alveolar rhabdomyosarcomas, we generated a Cre-mediated conditional knock-in of Pax3:Fkhr into the mouse Pax3 locus. Exploring embryonic tumor cell origins, we replaced a Pax3 allele with Pax3:Fkhr throughout its expression domain, causing dominant-negative effects on Pax3 and paradoxical activation of the Pax3 target gene, c-Met. Ectopic neuroprogenitor cell proliferation also occurs. In contrast, activation later in embryogenesis in cells that express Pax7 results in viable animals with a postnatal growth defect and a moderately decreased Pax7+ muscle satellite cell pool, phenocopying Pax7 deficiency but remarkably not leading to tumors.
authors.affiliation: Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of Utah, Salt Lake City, Utah 84112, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Keller
authors.forename: Mark S
authors.initials: MS
authors.lastname: Hansen
authors.forename: Cheryl M
authors.initials: CM
authors.lastname: Coffin
authors.forename: Mario R
authors.initials: MR
authors.lastname: Capecchi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D019426:Integrases / Q000235:genetics; D008636:Mesencephalon / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000254:growth & development / Q000473:pathology; D000072041:PAX3 Transcription Factor; D051763:PAX7 Transcription Factor; D051761:Paired Box Transcription Factors; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D018232:Rhabdomyosarcoma, Alveolar / Q000235:genetics* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D018398:Homeodomain Proteins; D000072041:PAX3 Transcription Factor; D051763:PAX7 Transcription Factor; D051761:Paired Box Transcription Factors; C497322:Pax7 protein, mouse; D014157:Transcription Factors; C068686:Pax3 protein, mouse; D019859:Proto-Oncogene Proteins c-met; C045073:Cre recombinase; D019426:Integrases