Targeted deletion of Wwox leads to postnatal lethality, impaired steroidogenesis and bone growth retardation

LB-380

WW domain-containing oxidoreductase (WWOX) encodes a 46kDa tumor suppressor. WWOX has two N-terminal WW domains, modules that mediate protein-protein interactions, and a central oxidoreductase domain that may be involved in steroid metabolism. WW domains mediate complexes associated with signaling pathways implicated in a variety of cellular processes such as transcriptional regulation and protein stability. We have previously shown that WWOX interacts with several transcriptional activators containing proline-tyrosine (PPxY) motifs, via its first WW domain. WWOX protein binds its ligands and prevents the interacting proteins from entering the nucleus, thus affecting transcriptional activation or repression. The nature of the various interacting partners with which the WWOX protein can physically associate suggest that WWOX plays a central role in different signal transduction pathways. To investigate WWOX function in vivo, we generated mice carrying a targeted disruption of the Wwox gene. Wwox-knockout (Wwox^-/-) mice die at the age of 3-4 weeks, are significantly reduced in size, and suffer of hypocalcemia, hypoglycemia and hypoproteinemia. In addition, mutant mice are born with gonadal abnormalities and displayed impaired steroidogenesis. Wwox^-/- mice also exhibit a delay in bone formation and develop metabolic bone disease. We found that WWOX physically associates with Runx2, the principal transcriptional regulator of osteoblast differentiation, and functionally suppresses Runx2 transactivation ability. Our data reveal a vital requirement for Wwox in postnatal survival and suggest a central role of Wwox in bone and steroid metabolism.