Cell migration is essential for embryonic development, wound healing processes and pathological conditions such as tumor metastasis. An understanding of the mechanism by which cells migrate cohesively in a directed manner will provide fundamental insights into the formation of tissues and organs and will help us understand how these mechanisms are applied during wound healing and go awry during cancer progression. We have developed a simple model system to study cohesive cell migration using the fruit fly Drosophila. In Drosophila, the combination of reverse and forward genetic approaches with the ability to study cell migration in an intact organism in real time allows us to identify genes involved in this process and understand the precise roles they play in cell migration. Due to the conservation of signaling networks between humans and invertebrate organisms, results of these studies can be applied to migration of human cells. Studies using cultured mammalian cells have revealed the mechanism by which single cells migrate in culture. Our current challenge is to understand whether such mechanisms also apply to cohesive cell migration and how cohesive cell migration differs from single cell migration. Here we focus on two unanswered questions concerning cohesive cell migration;1) how adhesion of migrating epithelial cells to the substratum is coordinated with cell-cell adhesion between cells and 2) how polarity is generated within the migrating cluster for net directed migration. Our first specific aim is to test the hypothesis that integrin-mediated adhesion between the migrating epithelial cells and the mesodermal cells upon which they migrate guide the initial migratory path of the epithelia by activating the small GTPase Rac.
Our second aim i s to test the hypothesis that Rac mediates migration of the advancing front and contraction of the rear of the epithelium. In our third and fourth aims we will identify and characterize two novel genes identified in a forward genetics screen for their roles in integrin-mediated adhesion during cohesive cell migration. Cell migration is essential for embryonic development, wound healing and tumor metastasis. We propose to study how cells migrate cohesively in the embryo so that we can apply our knowledge to design therapies to expedite or delay wound healing and prevent migration and invasion of cancer cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM082996-05
Application #
8231506
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Hoodbhoy, Tanya
Project Start
2008-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2012
Total Cost
$329,314
Indirect Cost
$133,294
Name
Weill Medical College of Cornell University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Pirraglia, Carolyn; Walters, Jenna; Ahn, Nancy et al. (2013) Rac1 GTPase acts downstream of ?PS1?PS integrin to control collective migration and lumen size in the Drosophila salivary gland. Dev Biol 377:21-32
Xu, Na; Bagumian, Gaiana; Galiano, Michael et al. (2011) Rho GTPase controls Drosophila salivary gland lumen size through regulation of the actin cytoskeleton and Moesin. Development 138:5415-27
Pirraglia, Carolyn; Walters, Jenna; Myat, Monn Monn (2010) Pak1 control of E-cadherin endocytosis regulates salivary gland lumen size and shape. Development 137:4177-89