The generation of cell polarity is a fundamental process that controls cell behavior during animal embryogenesis. In lower vertebrates, egg polarity plays an essential role in patterning the embryonic body. In mammals such as the mouse, however, the cellular polarization at the 8-cell stage is responsible for the formation of 2 different cell populations in the blastocyst: trophectoderm (TE) and inner cell mass (ICM). The outer, polarized cells give rise to TE, the founder of the placenta, while the inner, non-polarized cells become ICM, the founder of fetal tissues. Thus, the misregulation of cell polarization in the mammalian embryo could disrupt the cell lineages of the blastocyst, resulting in reproductive failure or disease due to aberrant development into embryo-derived cancer. The long-term goal of the proposed research is to elucidate the molecular mechanisms that initiate cell polarization in mouse early development, which is currently not well understood. A conserved molecular mechanism regulates cell polarity in various animal cells. This mechanism involves the partitioning defective (Par) genes, which were originally isolated in the nematode. Based on database searches of gene sequences, the investigator identified 18 Par homologs in the mouse genome. Our preliminary studies revealed that transcripts of many of the Par genes are expressed from the ovary to the blastocyst stage. The proposed project is a pilot study that will pursue one specific aim, which is to determine whether the Par genes are necessary for normal early development. The investigator will examine which of the 18 mouse Par genes are indispensable in early development, specifically with regards to cell polarization and TE/ICM development during blastocyst formation. She will employ the RNAi approach to down-regulate Par gene expression during early development. Thus, the project will clarify the importance of Par genes in establishing cell polarity and the first 2-cell lineages in the mouse embryo. An understanding of cell polarization in the mouse embryo should have significant benefit for human health research related to reproductive problems.

R03HD050475

2005-07-06

2008-06-30