During early mammalian development, a sequence of morphogenetic movements define the anterior-posterior body axis, create the germ layers, organize the midline and elongate the embryo to generate the correct spatial arrangement of tissues and organs. Little is known about how intercellular signals control these behaviors of cells and tissues during development. Here, genetic approaches are used to define the proteins and gene networks that regulate these morphogenetic events. A forward genetic screen has successfully identified a large number of chemically-induced mutations that disrupt morphogenesis of the embryo. The tools of mouse molecular genetics have been used to identify the genes responsible for the developmental defects of the mutants. Most of these genes had not been studied previously. This approach will be continued: additional mutants identified in the screen will be characterized and focused reporter-based screens will identify more of the genes that regulate embryonic morphogenesis. To move from single genes to the gene networks that regulate morphogenesis, experiments will determine how actin regulators identified in the screen are linked to developmental signals. Mutations identified in the screen will be used to define the gene networks that control morphogenesis in two embryonic tissues, the node and the neural plate. The embryonic node is required for organization of the midline and for left-right asymmetry. Both Notch signaling and the FERM domain protein Lulu/Epb4.1l5 are required for the proper formation of the node. Experiments will test whether Notch signaling controls node morphogenesis through Lulu-mediated actin rearrangements or if Lulu is required for Notch signaling. Closure of the neural plate into the neural tube depends on signaling by the planar polarity pathway. Genetic experiments suggest that Cofilin1, another actin regulator, may mediate planar polarity-dependent cell reorganization, and experiments will test this hypothesis. These studies will provide a foundation for understanding the genetic networks that link intercellular signals to cell behavior during mammalian development. Birth defects are caused by errors in morphogenesis. The proposed studies will define the genes and mechanisms that are responsible for congenital malformations such as situs inversus and neural tube defects. In addition, the same genes that direct embryonic morphogenesis are of critical importance in metastasis. For example, Cofilin1 and other actin regulators are upregulated during metastasis and promote the movement of tumor cells. The proposed studies will define how these actin regulators function in the intact embryos and tissues, which is certain to parallel their roles in tumor metastasis.
Normal mammalian development and the abnormal development of tumors are regulated by intercellular signals that direct cell migration and cell rearrangements. Disruption of these processes leads to birth defects and metastasis. Genetic experiments will define proteins and gene networks that regulate cell behavior in response to extracellular signals during mammalian development.
|Grego-Bessa, Joaquim; Bloomekatz, Joshua; Castel, Pau et al. (2016) The tumor suppressor PTEN and the PDK1 kinase regulate formation of the columnar neural epithelium. Elife 5:e12034|
|Ramkumar, Nitya; Harvey, Beth M; Lee, Jeffrey D et al. (2015) Protein O-Glucosyltransferase 1 (POGLUT1) Promotes Mouse Gastrulation through Modification of the Apical Polarity Protein CRUMBS2. PLoS Genet 11:e1005551|
|Grego-Bessa, Joaquim; Hildebrand, Jeffrey; Anderson, Kathryn V (2015) Morphogenesis of the mouse neural plate depends on distinct roles of cofilin 1 in apical and basal epithelial domains. Development 142:1305-14|
|Bangs, Fiona K; Schrode, Nadine; Hadjantonakis, Anna-Katerina et al. (2015) Lineage specificity of primary cilia in the mouse embryo. Nat Cell Biol 17:113-22|
|Bazzi, Hisham; Anderson, Kathryn V (2014) Acentriolar mitosis activates a p53-dependent apoptosis pathway in the mouse embryo. Proc Natl Acad Sci U S A 111:E1491-500|
|Handschuh, Karen; Feenstra, Jennifer; Koss, Matthew et al. (2014) ESCRT-II/Vps25 constrains digit number by endosome-mediated selective modulation of FGF-SHH signaling. Cell Rep 9:674-87|
|Omelchenko, Tatiana; Rabadan, M Angeles; HernÃ¡ndez-MartÃnez, RocÃo et al. (2014) Î²-Pix directs collective migration of anterior visceral endoderm cells in the early mouse embryo. Genes Dev 28:2764-77|
|Mahaffey, James P; Grego-Bessa, Joaquim; Liem Jr, Karel F et al. (2013) Cofilin and Vangl2 cooperate in the initiation of planar cell polarity in the mouse embryo. Development 140:1262-71|
|Bloomekatz, Joshua; Grego-Bessa, Joaquim; Migeotte, Isabelle et al. (2012) Pten regulates collective cell migration during specification of the anterior-posterior axis of the mouse embryo. Dev Biol 364:192-201|
|Laird, Diana J; Altshuler-Keylin, Svetlana; Kissner, Michael D et al. (2011) Ror2 enhances polarity and directional migration of primordial germ cells. PLoS Genet 7:e1002428|
Showing the most recent 10 out of 17 publications