Research Article: Generation and Characterization of Mice Carrying a Conditional Allele of the Wwox Tumor Suppressor Gene

Date Published: November 10, 2009

Publisher: Public Library of Science

Author(s): John H. Ludes-Meyers, Hyunsuk Kil, Jan Parker-Thornburg, Donna F. Kusewitt, Mark T. Bedford, C. Marcelo Aldaz, Alfons Navarro.

Abstract: 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 hematopoeisis, leukopenia, and splenic atrophy. Impaired hematopoeisis 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.

Partial Text: WW domain-containing oxidoreductase (WWOX) was cloned and identified as a potential tumor suppressor gene mapping to the chromosome region 16q23 [1]. The WWOX gene spans >1.1 Mb and overlaps the common chromosomal fragile site, FRA16D, the second most common site for chromosomal breakage, instability and rearrangement of the whole genome [1]–[3]. Allelic losses and rearrangements affecting the WWOX locus have been described in various human cancers [1]–[5]. Additionally, various studies have reported significant loss of WWOX expression in multiple human neoplasias including breast, prostate, ovarian, lung and liver cancer [6], [7].

The WWOX tumor suppressor gene is inactivated in many types of human cancers by genomic rearrangements, aberrant mRNA splicing, homozygous deletions and epigenetic silencing [1]–[5], [24]. Because Wwox KO mice do not survive to adulthood previous studies of Wwox tumor suppression required chemical carcinogen treatment of Wwox+/− mice [20]. Therefore, we have generated mice carrying a conditional allele of the Wwox tumor suppressor gene.



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