Generation and characterization of mice carrying a conditional allele of the Wwox tumor suppressor gene.
WWOX, the gene that spans the second most common human chromosomal fragile site, FRA16D, is inactivated in multiple human cancers and behaves as a suppressor of tumor growth. Since we are interested in understanding WWOX function in both normal and cancer tissues we generated mice harboring a conditional Wwox allele by flanking Exon 1 of the Wwox gene with LoxP sites. Wwox knockout (KO) mice were developed by breeding with transgenic mice carrying the Cre-recombinase gene under the control of the adenovirus EIIA promoter. We found that Wwox KO mice suffered from severe metabolic defect(s) resulting in growth retardation and all mice died by 3 wk of age. All Wwox KO mice displayed significant hypocapnia suggesting a state of metabolic acidosis. This finding and the known high expression of Wwox in kidney tubules suggest a role for Wwox in acid/base balance. Importantly, Wwox KO mice displayed histopathological and hematological signs of impaired hematopoiesis, leukopenia, and splenic atrophy. Impaired hematopoiesis can also be a contributing factor to metabolic acidosis and death. Hypoglycemia and hypocalcemia was also observed affecting the KO mice. In addition, bone metabolic defects were evident in Wwox KO mice. Bones were smaller and thinner having reduced bone volume as a consequence of a defect in mineralization. No evidence of spontaneous neoplasia was observed in Wwox KO mice. We have generated a new mouse model to inactivate the Wwox tumor suppressor gene conditionally. This will greatly facilitate the functional analysis of Wwox in adult mice and will allow investigating neoplastic transformation in specific target tissues.
Ludes-Meyers
John H
JH
Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas, United States of America.
Kil
Hyunsuk
H
Parker-Thornburg
Jan
J
Kusewitt
Donna F
DF
Bedford
Mark T
MT
Aldaz
C Marcelo
CM
D000483:Alleles; D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D019426:Integrases / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010088:Oxidoreductases / Q000235:genetics*; D000074584:WW Domain-Containing Oxidoreductase
D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C428130:Wwox protein, mouse; C045073:Cre recombinase; D019426:Integrases