Search

The placenta plays a critical role in the growth and survival of the fetus. Here we demonstrate that the Homologous to the E6-AP Carboxyl Terminus (HECT) domain E3 ubiquitin ligase, Hectd1, is essential for development of the mouse placenta. Hectd1 is widely expressed during placentation with enrichment in trophoblast giant cells (TGCs) and other trophoblast-derived cell subtypes in the junctional and labyrinth zones of the placenta. Disruption of Hectd1 results in mid-gestation lethality and intrauterine growth restriction (IUGR). Variable defects in the gross structure of the mutant placenta are found including alterations in diameter, thickness and lamination. The number and nuclear size of TGCs is reduced. Examination of subtype specific markers reveals altered TGC development with decreased expression of Placental lactogen-1 and -2 (Pl1 and Pl2) and increased expression of Proliferin (Plf). Reduced numbers of spongiotrophoblasts and glycogen trophoblasts were also found at the junctional zone of the Hectd1 mutant placenta. Finally, there was an increase in immature uterine natural killer (uNK) cells in the maternal decidua of the Hectd1 mutant placenta. Proliferation and apoptosis are differentially altered in the layers of the placenta with an increase in both apoptosis and proliferation in the maternal decidua, a decrease in proliferation and increase in apoptosis in the labyrinth layer and both unchanged in the junctional zone. Together these data demonstrate that Hectd1 is required for development of multiple cell types within the junctional zone of the placenta.

Understanding the lineage relationship between normal progenitor cells and cell type(s) of origin for cancer may yield important molecular insights into prostate cancer prognosis and treatment response. For example, several studies have suggested that the prostate basal epithelial compartment contains stem/progenitor cells that can be transformed to initiate cancers in tissue reconstitution assays. In our work, we have shown that a known regulator of prostate epithelial differentiation, the homeobox gene Nkx3.1, marks a luminal stem cell population that functions during prostate regeneration. Genetic lineage-tracing studies demonstrate that rare cells which express Nkx3.1 in the absence of testicular androgens (castration-resistant Nkx3.1-expressing cells, CARNs) are bipotential and can self-renew in vivo, while single-cell transplantation assays show that CARNs can reconstitute prostate ducts in renal grafts. Targeted deletion of the Pten tumor suppressor gene in CARNs results in rapid formation of carcinoma following androgen-mediated regeneration. These observations indicate that CARNs represent a novel luminal stem cell population that is an efficient target for oncogenic transformation in prostate cancer. In our ongoing work, we are investigating the properties of CARNs as well as other epithelial cell types during prostate regeneration and as cells of origin for cancer in vivo. In particular, we have utilized CK5-CreERT2 transgenic mice for lineage-tracing of basal cells during androgen-mediated prostate regeneration and oncogenic transformation. We will present our recent findings and discuss their implications with respect to elucidating the prostate epithelial lineage hierarchy and its relationship to cancer initiation.