Pax3-FKHR knock-in mice show developmental aberrations but do not develop tumors

Irina Lagutina, Simon Conway, Jack Sublett, Gerard C. Grosveld

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Alveolar rhabdomyosarcoma is a pediatric disease specified by the recurrent chromosome translocations t(2;13) and t(1;13). These translocations result in the formation of the PAX3-FKHR and PAX7-FKHR fusion genes, which are thought to play a causal role in the genesis of this disease. Although PAX3-FKHR exhibits transforming activity in immortalized fibroblast cell lines, a direct role of this fusion protein in tumorigenesis in vivo has not been shown. We determined whether expression of Pax3-FKHR in the mouse germ line would render these animals prone to the development of rhabdomyosarcomas. By targeting FKHR cDNA sequences into the Pax3 locus of embryonic stem cells, we used these cells to generate mice carrying a Pax3-FKHR knock-in allele. Despite low expression of the knock-in allele, heterozygous offspring of Pax3-FKHR chimeric mice showed developmental abnormalities. These included intraventricular septum defects, tricuspid valve insufficiency, and diaphragm defects, which caused congestive heart failure leading to perinatal death. In addition, Pax3-FKHR heterozygous offspring displayed malformations of some but not all hypaxial muscles. However, neither newborn heterozygous pups nor their chimeric parents showed any signs of malignancy. We conclude that the Pax3-FKHR allele causes lethal developmental defects in knock-in mice but might be insufficient to cause muscle tumors.

Original languageEnglish (US)
Pages (from-to)7204-7216
Number of pages13
JournalMolecular and Cellular Biology
Volume22
Issue number20
DOIs
StatePublished - Oct 2002
Externally publishedYes

Fingerprint

Neoplasms
Alleles
Alveolar Rhabdomyosarcoma
Lethal Genes
Tricuspid Valve Insufficiency
Muscles
Rhabdomyosarcoma
Gene Fusion
Embryonic Stem Cells
Diaphragm
Germ Cells
Carcinogenesis
Heart Failure
Complementary DNA
Fibroblasts
Chromosomes
Pediatrics
Cell Line
Proteins
Perinatal Death

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Pax3-FKHR knock-in mice show developmental aberrations but do not develop tumors. / Lagutina, Irina; Conway, Simon; Sublett, Jack; Grosveld, Gerard C.

In: Molecular and Cellular Biology, Vol. 22, No. 20, 10.2002, p. 7204-7216.

Research output: Contribution to journalArticle

Lagutina, Irina ; Conway, Simon ; Sublett, Jack ; Grosveld, Gerard C. / Pax3-FKHR knock-in mice show developmental aberrations but do not develop tumors. In: Molecular and Cellular Biology. 2002 ; Vol. 22, No. 20. pp. 7204-7216.
@article{10f242f8a43e4499a805f1254e8d1847,
title = "Pax3-FKHR knock-in mice show developmental aberrations but do not develop tumors",
abstract = "Alveolar rhabdomyosarcoma is a pediatric disease specified by the recurrent chromosome translocations t(2;13) and t(1;13). These translocations result in the formation of the PAX3-FKHR and PAX7-FKHR fusion genes, which are thought to play a causal role in the genesis of this disease. Although PAX3-FKHR exhibits transforming activity in immortalized fibroblast cell lines, a direct role of this fusion protein in tumorigenesis in vivo has not been shown. We determined whether expression of Pax3-FKHR in the mouse germ line would render these animals prone to the development of rhabdomyosarcomas. By targeting FKHR cDNA sequences into the Pax3 locus of embryonic stem cells, we used these cells to generate mice carrying a Pax3-FKHR knock-in allele. Despite low expression of the knock-in allele, heterozygous offspring of Pax3-FKHR chimeric mice showed developmental abnormalities. These included intraventricular septum defects, tricuspid valve insufficiency, and diaphragm defects, which caused congestive heart failure leading to perinatal death. In addition, Pax3-FKHR heterozygous offspring displayed malformations of some but not all hypaxial muscles. However, neither newborn heterozygous pups nor their chimeric parents showed any signs of malignancy. We conclude that the Pax3-FKHR allele causes lethal developmental defects in knock-in mice but might be insufficient to cause muscle tumors.",
author = "Irina Lagutina and Simon Conway and Jack Sublett and Grosveld, {Gerard C.}",
year = "2002",
month = "10",
doi = "10.1128/MCB.22.20.7204-7216.2002",
language = "English (US)",
volume = "22",
pages = "7204--7216",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "20",

}

TY - JOUR

T1 - Pax3-FKHR knock-in mice show developmental aberrations but do not develop tumors

AU - Lagutina, Irina

AU - Conway, Simon

AU - Sublett, Jack

AU - Grosveld, Gerard C.

PY - 2002/10

Y1 - 2002/10

N2 - Alveolar rhabdomyosarcoma is a pediatric disease specified by the recurrent chromosome translocations t(2;13) and t(1;13). These translocations result in the formation of the PAX3-FKHR and PAX7-FKHR fusion genes, which are thought to play a causal role in the genesis of this disease. Although PAX3-FKHR exhibits transforming activity in immortalized fibroblast cell lines, a direct role of this fusion protein in tumorigenesis in vivo has not been shown. We determined whether expression of Pax3-FKHR in the mouse germ line would render these animals prone to the development of rhabdomyosarcomas. By targeting FKHR cDNA sequences into the Pax3 locus of embryonic stem cells, we used these cells to generate mice carrying a Pax3-FKHR knock-in allele. Despite low expression of the knock-in allele, heterozygous offspring of Pax3-FKHR chimeric mice showed developmental abnormalities. These included intraventricular septum defects, tricuspid valve insufficiency, and diaphragm defects, which caused congestive heart failure leading to perinatal death. In addition, Pax3-FKHR heterozygous offspring displayed malformations of some but not all hypaxial muscles. However, neither newborn heterozygous pups nor their chimeric parents showed any signs of malignancy. We conclude that the Pax3-FKHR allele causes lethal developmental defects in knock-in mice but might be insufficient to cause muscle tumors.

AB - Alveolar rhabdomyosarcoma is a pediatric disease specified by the recurrent chromosome translocations t(2;13) and t(1;13). These translocations result in the formation of the PAX3-FKHR and PAX7-FKHR fusion genes, which are thought to play a causal role in the genesis of this disease. Although PAX3-FKHR exhibits transforming activity in immortalized fibroblast cell lines, a direct role of this fusion protein in tumorigenesis in vivo has not been shown. We determined whether expression of Pax3-FKHR in the mouse germ line would render these animals prone to the development of rhabdomyosarcomas. By targeting FKHR cDNA sequences into the Pax3 locus of embryonic stem cells, we used these cells to generate mice carrying a Pax3-FKHR knock-in allele. Despite low expression of the knock-in allele, heterozygous offspring of Pax3-FKHR chimeric mice showed developmental abnormalities. These included intraventricular septum defects, tricuspid valve insufficiency, and diaphragm defects, which caused congestive heart failure leading to perinatal death. In addition, Pax3-FKHR heterozygous offspring displayed malformations of some but not all hypaxial muscles. However, neither newborn heterozygous pups nor their chimeric parents showed any signs of malignancy. We conclude that the Pax3-FKHR allele causes lethal developmental defects in knock-in mice but might be insufficient to cause muscle tumors.

UR - http://www.scopus.com/inward/record.url?scp=0036787919&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036787919&partnerID=8YFLogxK

U2 - 10.1128/MCB.22.20.7204-7216.2002

DO - 10.1128/MCB.22.20.7204-7216.2002

M3 - Article

VL - 22

SP - 7204

EP - 7216

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 20

ER -