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affect the gastrulation EMT, including mutations that affect genes involved in Wnt signaling (Qian et al. 2011, and unpublished), mesoderm migration (Rakeman et al., 2006, and unpublished), the gastrulation EMT (Lee et al., 2007; and unpublished) and epithelial organization (Lee et al., 2007 and unpublished).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

Ramkumar N, Omelchenko T, Silva-Gagliardi NF, McGlade CJ, Wijnholds J, Anderson KV. (2016) Crumbs2 promotes cell ingression during the epithelial-to-mesenchymal transition at gastrulation. Nat Cell Biol. 18: 1281-1291.

Grego-Bessa J, Bloomekatz J, Castel P, Omelchenko T, Baselga J, Anderson KV. (2016) The tumor suppressor PTEN and the PDK1 kinase regulate formation of the columnar neural epithelium. Elife. Jan 26; 5. pii:e12034.

Ramkumar N, Harvey BM, Lee JD, Alcorn HL, Silva-Gagliardi NF, McGlade CJ, Bestor TH, Wijnholds J, Haltiwanger RS, Anderson KV. (2015) Protein O-Glucosyltransferase 1 (POGLUT1) Promotes Mouse Gastrulation through Modification of the Apical Polarity Protein CRUMBS2. PLoS Genet. Oct  23; 11(10):e1005551.

Grego-Bessa J, Hildebrand J, Anderson KV. (2015) Morphogenesis of the mouse neural plate depends on distinct roles of cofilin 1 in apical and basal epithelial domains. Development. 142: 1305-1314.

Omelchenko T, Rabadan MA, Hernández-Martínez R, Grego-Bessa J, Anderson KV, Hall A. (2014) β-Pix directs collective migration of anterior visceral endoderm cells in the early mouse embryo. Genes Dev. 28: 2764-77.

Mahaffey, J. P., Grego-Bessa, J., Liem, K. F. Jr. and Anderson, K. V. (2013) Cofilin and Vangl2 cooperate in the initiation of planar cell polarity in the mouse embryo. Development 140: 1262-1271.

Bloomekatz. J., Grego-Bessa, J., Migeotte, I. and Anderson, K. V. (2012) Pten regulates collective cell migration during specification of the anterior-posterior axis of the mouse embryo. Dev Biol. 364: 192-201.

Migeotte, I., Grego-Bessa, J. and Anderson, K. V. (2011) Rac1 mediates morphogenetic responses to intercellular signals in the gastrulating mouse embryo. Development. 138: 3011-3020.

Qian, L. Mahaffey, J. P., Alcorn, H. L. and Anderson, K. V. (2011) Tissue-specific roles of Axin2 in the inhibition and activation of Wnt signaling in the mouse embryo. Proc. Natl. Acad. Sci. USA. 108: 8692-8697.

Migeotte, I., Omelchenko, T., Hall, A., Anderson, K.V. (2010) Rac1-dependent collective cell migration is required for specification of the anterior-posterior body axis of the mouse. PLoS Biol. 8:e1000442.

Garcia-Garcia, M. J., Shibata, M. and Anderson, K. V. (2008) Chato, a KRAB Zinc Finger Protein, Regulates Convergent Extension in the Mouse Embryo. Development. 135: 3053-3062.

Lee, J. D., Silva-Gagliardi, N. F., Tepass, U., McGlade, C. J. and Anderson, K. V. (2007) The FERM protein Epb4.1l5 is required for organization of the neural plate and the epithelial-mesenchymal transition at the primitive streak of the mouse embryo. Development. 134: 2007-2016.

Rakeman, A. S. and Anderson, K. V. (2006) Axis specification and morphogenesis in the mouse embryo require Nap1, a regulator of WAVE-mediated actin branching. Development. 133: 3075-3083.

Garcia-Garcia, M. J., Eggenschwiler, J. T., Caspary, T., Alcorn, H. L., Wyler, M. R., Huangfu, D., Rakeman, A. S., Lee, J. D., Feinberg, E. H, Timmer, J. R. and Anderson, K. V. (2005) Analysis of mouse embryonic patterning and morphogenesis by forward genetics. Proc. Natl. Acad. Sci. USA. 102: 5913-5919.