The role of murine Dishevelled in mammary development and Wnt-mediated tumorigenesis

Abstract

The Wnt-1 proto-oncogene is one of the most frequently activated genes in mouse mammary tumor virus (MMTV)-derived breast tumors. Wnt-1 is a member of a family of genes that display complex patterns of expression during embryogenesis and have been shown to be required for central nervous system, kidney, limb, and placenta development. Several Wnt genes are expressed in the developing mouse mammary gland. The Wnt-1 product is a secreted glycoprotein that has been implicated in cell signaling. The identification of the Drosophila Wnt-1 homologue, wingless (wg ), a segment polarity gene, has enabled the components of the Wnt/wg intracellular pathway to be identified. To date, dishevelled (dsh) has been identified as the most upstream component of wg signaling subsequent to receptor activation and encodes a cytoplasmic protein required for interpretation of the wg signal. Three mammalian homologues of dsh, Dvl1, Dvl2 and Dvl3 , have been identified and characterized. Each exhibits expression patterns in embryonic and adult mice that are consistent with a role in Wnt signal transduction.;Based on the observation that Wnt-1 expressed ectopically in the mammary glands of transgenic mice causes extensive hyperplasia and mammary adenocarcinomas, we have generated three lines of FVB/N mice that harbor an MMTV LTR Dvl2-myc expression construct in their genome. Concomitantly, we have generated an additional transgenic FVB/N line with a putative dominant-negative MMTV Dvl2-myc construct (MMTVDeltaPDZ Dvl2-myc). We anticipated that replication of the Wnt-1 mammary phenotype in the MMTV Dvl2-myc animals, or, alternatively, modification of the phenotype in double transgenic MMTV Wnt-1/MMTVDeltaPDZDvl2-myc mice, would confirm a role for murine Dvl in Wnt signaling. The resultant MMTV Dvl2-myc and MMTV DeltaPDZ Dvl2-myc transgenic mice are viable, fertile, and exhibit no lactation defects. Western blot and RT-PCR analyses have confirmed that heterozygous transgenic mice express the Dvl2-myc-encoded protein and mRNA in their mammary and salivary glands; we have been unable to demonstrate expression in the DeltaPDZDvl2-myc line. Gross and histological examinations of glands isolated from virgin, pregnant and multiparous MMTV Dvl2-myc females have revealed no significant differences between these tissues and those harvested from wild-type littermates. A single mammary lipoma and two neuroectodermal tumors involving the uterus have been detected in aged multiparous MMTV Dvl2-myc females; no transgene expression has been associated with the uterine tumors, however, and all have been considered sporadic events. While we have been unable to document changes in the mammary gland upon ectopic expression of our transgene, the lack of a phenotype does not exclude a role for Dvl2 in normal mammary development and Wnt-mediated tumorigenesis.