Molecular Genetics and Systems Biology of Placental Development and Metabolism

Description of projects available to graduate students:
Starting over twelve years ago with a placental-lethal phenotype of the nuclear receptor PPARγ, our group has used mouse genetics and functional genomics to generate critical insights and challenge existing dogmas in the placenta field. Current projects that are based on these tools and leads include:
1. Molecular genetics of placental intermediary metabolism – we identified what appears to be a novel PPARγ-regulated biosynthetic pathway that converts lactate to lipids. PPARγ regulates at least four, and likely more, enzymes in this pathway. Graduate students could undertake ongoing gene targeting projects that disrupt the two rate-limiting enzymes in this putative pathway, en route to comprehensive characterization of the metabolic and developmental consequences.
2. Molecular genetics of placental fuel export – following the analysis of target gene promoters, we identified a novel transcription cofactor of PPARγ. Subsequent knockout of this cofactor revealed a novel neonatal lethal defect that is associated with obstructed release of placental glycogen to the late embryo. Graduate students could undertake tissue-specific gene targeting experiments and analysis of target promoters of PPARγ-regulated genes to better understand the molecular and developmental basis of this newly discovered process.

Techniques graduate student will learn:
• Gene targeting: construct design, recombineering, ES cell targeting, embryo manipulation, complex genetic crosses.
• Gene expression analysis: qPCR, transfections, reporter analysis, Blotting (Northern, Western), in situ hybridization, immunodetection.
• Cell culture: ES cells, trophoblast stem (TS) cells, primary fibroblasts.
• Histology and Imaging: microdissection, sectioning, light and fluorescent microscopy.