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.

Public Health Relevance

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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Javois, Lorette Claire
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Sloan-Kettering Institute for Cancer Research
New York
United States
Zip Code
Bazzi, Hisham; Soroka, Ekaterina; Alcorn, Heather L et al. (2017) STRIP1, a core component of STRIPAK complexes, is essential for normal mesoderm migration in the mouse embryo. Proc Natl Acad Sci U S A 114:E10928-E10936
Jain, Devanshi; Meydan, Cem; Lange, Julian et al. (2017) rahu is a mutant allele of Dnmt3c, encoding a DNA methyltransferase homolog required for meiosis and transposon repression in the mouse male germline. PLoS Genet 13:e1006964
Castel, Pau; Carmona, F Javier; Grego-Bessa, Joaquim et al. (2016) Somatic PIK3CA mutations as a driver of sporadic venous malformations. Sci Transl Med 8:332ra42
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; Omelchenko, Tatiana; Silva-Gagliardi, Nancy F et al. (2016) Crumbs2 promotes cell ingression during the epithelial-to-mesenchymal transition at gastrulation. Nat Cell Biol 18:1281-1291
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
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
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
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
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

Showing the most recent 10 out of 22 publications