This proposal tests the hypothesis that the classical cadherins, in addition to their known role in cell-cell adhesion, also control morphogenetic tissue movements in the vertebrate embryo, by controlling the assembly of cortical actin. Cadherins are a large family of proteins, which are expressed in different combinations in different tissues of the embryo as they form. We propose that the combination of different cadherins, and the different cellular contexts in which they are expressed, together generate cortical actin networks with different motile and adhesive properties. This results in the characteristic differences in tissue shapes that arise in the embryo. This hypothesis, which is supported by extensive preliminary data and published work, will be tested in the early Xenopus embryonic ectoderm, which arises from the animal region of the blastula. We have shown previously that the cortical actin filament network in the blastula, which is essential for overall shape and rigidity of the whole embryo, requires the expression of C-cadherin on the cell surface. As the ectoderm differentiates, the neural and non-neural ectoderm express different combinations of cadherins, and dramatic changes in tissue movement accompany these changes in expression. We will test the central hypothesis by manipulating the expression of individual cadherins, or component domains, in the wrong tissues, compare the actin assembly proteins that bind to them, and test the functions of those that bind differentially to different cadherins. In previous work, we showed that signaling by phospholipids is essential for cortical actin assembly in the blastula. We will test the hypothesis that it continues to be required for actin assembly in the ectodermal tissues derived from the blastula.

Public Health Relevance

This project aims to identify the molecular mechanisms that coordinate cell adhesion and cell motility as the organs of the body first form. Many birth defects are caused by failure of cell adhesion and tissue movement, and so a molecular understanding of the way they occur is important and timely.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD044764-09
Application #
8220846
Study Section
Cell Structure and Function (CSF)
Program Officer
Ravindranath, Neelakanta
Project Start
2003-07-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
9
Fiscal Year
2012
Total Cost
$295,812
Indirect Cost
$98,604
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229