This proposal concerns molecular mechanisms leading to the formation of apically constricted cells in the vertebrate embryo. Apical constrictio is a process, during which the apical surface of a cell is reduced causing the cell to take on a wedged shape. These coordinated cell shape changes drive many morphogenetic processes throughout development, however, little is known about how apical constriction is regulated at the cellular and molecular level. Our preliminary studies of blastopore formation at the onset of Xenopus gastrulation identified specific candidate regulators of apical constriction and revealed a connection to Wnt signaling. We propose to identify novel components of the apical constriction pathway and evaluate the requirement for the identified candidate molecules in blastopore formation during gastrulation. These experiments will be carried out in Xenopus embryos, which are uniquely suited for biochemical, cell biological and functional analysis of this process in vivo. An unbiased and candidate-based expression cloning approach will be carried out to identify novel regulators of apical constriction and their role in apical constriction will e confirmed in loss-of-function studies. Based on epistatic analysis, these new molecular players will be positioned in a molecular pathway that leads to coordinate spatial regulation of Rho signaling and actomyosin contractility in the apical domains of epithelial cells. The proposed experiments will reconstruct molecular pathways leading to apical constriction in vertebrate epithelial cells during early development and establish a novel function for PCP proteins in apical constriction. These studies will contribute to the knowledge necessary for prevention of birth abnormalities such as neural tube closure defects and will be relevant to human cancer disease.

Public Health Relevance

This proposal concerns molecular mechanisms leading to apical constriction, a morphogenetic process that controls tissue folding during embryonic development. The proposed studies will contribute to the knowledge necessary for prevention of birth abnormalities, such as neural tube defects, and are relevant to human cancers.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HD078874-01A1
Application #
8769020
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Mukhopadhyay, Mahua
Project Start
2014-09-01
Project End
2016-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Biology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10029
Sokol, Sergei Y (2016) Mechanotransduction During Vertebrate Neurulation. Curr Top Dev Biol 117:359-76
Ossipova, Olga; Chuykin, Ilya; Chu, Chih-Wen et al. (2015) Vangl2 cooperates with Rab11 and Myosin V to regulate apical constriction during vertebrate gastrulation. Development 142:99-107
Ossipova, Olga; Kim, Kyeongmi; Sokol, Sergei Y (2015) Planar polarization of Vangl2 in the vertebrate neural plate is controlled by Wnt and Myosin II signaling. Biol Open 4:722-30
Ossipova, Olga; Chu, Chih-Wen; Fillatre, Jonathan et al. (2015) The involvement of PCP proteins in radial cell intercalations during Xenopus embryonic development. Dev Biol 408:316-27
Sokol, Sergei Y (2015) Spatial and temporal aspects of Wnt signaling and planar cell polarity during vertebrate embryonic development. Semin Cell Dev Biol 42:78-85