During early nnammalian development, a sequence of nnorphogenetic moveirients 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. A forward genetic screen has successfully identified a large number of novel chemically-induced mutations that disrupt morphogenesis ofthe embryo. SNP-based mapping and next generation sequencing have made it possible to rapidly identify the genes responsible for the developmental defects of the mutants. Additional morphogenesis mutants will be identified in focused, reporter-based screens. Building on the mutations that have been identified, experiments will define the mechanisms that control two key events in early development, establish the anterior-posterior body axis, and the epithelial-to- mesenchymal transition (EMT) that generates the three layers of the embryo during gastrulation. Experiments will test whether elevated Wnt signaling is necessary, but not sufficient, to generate ectopic body axes, and whether Axin1, p120-catenin and Usp8 work together to restrict the ability of cells in the epiblast to give rise to the pluripotent cells ofthe primitive streak. Data suggest that although the EMT involves loss of apical-basal polarity, a set of apical-basal polarity proteins is required for the gastrulation EMT. To understand the paradoxical requirement for apical-basal polarity in the EMT, conditional gene deletion will be used to determine which cells require the activity of polarity proteins and fluorescently tagged apical proteins will be used to follow the fate of apical junction proteins during the EMT. The proposed studies will define the genes and mechanisms that are responsible for congenital malformations such as situs inversus, microcephaly, and heart defects. The same genes discovered for their role in embryonic morphogenesis are likely to be critical importance in tumorigenesis and metastasis.

Public Health Relevance

Normal mammalian development is regulated by intercellular signals that direct cell migration and cell rearrangements. Genetic experiments will identify and characterize genes that couple signaling molecules to cell behavior that are important in birth defects. Based on past experience, the genes identified in the embryo will play important roles in tumorigenesis and metastasis.

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
Special Emphasis Panel (NSS)
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
Jain, Devanshi; Puno, M Rhyan; Meydan, Cem et al. (2018) ketu mutant mice uncover an essential meiotic function for the ancient RNA helicase YTHDC2. Elife 7:
Agbu, Stephanie O; Liang, Yinwen; Liu, Aimin et al. (2018) The small GTPase RSG1 controls a final step in primary cilia initiation. J Cell Biol 217:413-427
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
Bangs, Fiona; Anderson, Kathryn V (2017) Primary Cilia and Mammalian Hedgehog Signaling. Cold Spring Harb Perspect Biol 9:
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
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

Showing the most recent 10 out of 25 publications