Gastrulation and Cell Migration

Many of the important events that define the body plan in the early mouse embryo unfold in one day of gestation, between e7.5 and e8.5 (Fig. 1)

Mouse embryo between embryonic day 7.5 and 8.5.

We focus on the signals and molecules that regulate the epithelial-to-mesenchymal transition (EMT) at gastrulation and subsequent migration of the mesoderm. The gastrulation EMT takes place at a single position in the early embryo, the primitive streak, where Wnt, Nodal and Fgf signals converge. At the streak, cells transform from an epithelium (the epiblast) into migrating mesenchymal cells (the mesoderm).

Figure 2.  The primitive streak in the e7.5 embryo (left) forms at a single position at the posterior of the embryo embryonic circumference, where Wnt, Nodal and Fgf signals converge. Under the influence of these signals, cells change their fate from ectodermal to mesoderm/endoderm and change their cellular organization from epithelial to mesenchymal.
Figure 3.  A scanning electron micrograph (SEM) showing the transformation in morphology between cells in the epiblast and the mesoderm. The mesodermal cells arise from the gastrulation EMT and migrate around the entire circumference of the embryo.

We have many isolated novel mutants that affect the gastrulation EMT, including mutations that affect genes involved in Wnt signaling (Qian et al. 2011, and unpublished), mesoderm migration (Rakeman et al., 2006, and unpublished), the gastrulation EMT (Lee et al., 2007; and unpublished) and epithelial organization (Lee et al., 2007 and unpublished).

These same genes are re-used again throughout development and in tumors, and we study those genes in those contexts as well. For example, we showed that a mutation that stabilizes Axin2, a regulator of Wnt signaling, blocks canonical Wnt signaling in most tissues but enhances Wnt signaling in the late primitive streak. Because activated Wnt signaling drives human colon cancer, we are testing how stabilization of Axin2 affects intestinal cancer in a mouse model; preliminary data suggest that stabilization of Axin2 may enhance tumorigenesis. We are also testing whether regulators of mesoderm migration affect metastasis in mouse tumor models.