Cell migration is a major driving force in embryonic development, wound healing, and tumor metastasis. Therefore, understanding the molecular mechanisms that control cell motility is significant for human health. My laboratory has developed a relatively simple and genetically tractable model for the study of cell migration, the movement of a small group of cells in the Drosophila ovary known as the border cells. In the previous funding period we have identified and characterized a number of new border cell migration genes. We also overcame a major technical obstacle and succeeded in time-lapse, live-imaging of migrating border cells. We propose to build upon these advances to address a major unsolved question in the field of cell migration: how cell polarity and cytoskeletal dynamics are integrated to achieve coordinated, directed migration of a group of cells. To address this general question, we will combine genetic approaches, live-imaging and biochemistry with two specific aims. The first is to test the hypothesis that a protein we have named FAV, and its mammalian homologs, amplify EGFR-dependent cell polarity and integrate EGFR signaling, trafficking and cell polarity with actin dynamics.
The second aim i s to test the hypothesis that a newly identified protein, Tiarin, and its human homolog, are conserved regulators of actin dynamics and cell motility. Together these studies will provide insights into the mechanisms controlling border cell migration, correlate the findings with the broader field of actin dynamics, and use this model to identify and characterize genes important in human health and disease.

Public Health Relevance

The ability to move is a property of cells from virtually all animals, from simple ones such as flies and worms, all the way to humans. The proposed research focuses on the movement of a small group of cells in the fruitfly, to learn more about how specific molecules orchestrate when, where and how they move. Since cell motility contributes to wound healing and tumor metastasis, these studies could lead to the discovery of new drug targets that could promote healing or inhibit the spread of cancer cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM073164-08
Application #
8212377
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Hoodbhoy, Tanya
Project Start
2005-02-01
Project End
2013-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
8
Fiscal Year
2012
Total Cost
$353,620
Indirect Cost
$137,998
Name
Johns Hopkins University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Cai, Danfeng; Chen, Shann-Ching; Prasad, Mohit et al. (2014) Mechanical feedback through E-cadherin promotes direction sensing during collective cell migration. Cell 157:1146-59
Koride, Sarita; He, Li; Xiong, Li-Ping et al. (2014) Mechanochemical regulation of oscillatory follicle cell dynamics in the developing Drosophila egg chamber. Mol Biol Cell 25:3709-16
Ramel, Damien; Wang, Xiaobo; Laflamme, Carl et al. (2013) Rab11 regulates cell-cell communication during collective cell movements. Nat Cell Biol 15:317-24
Wu, Yi I; Wang, Xiaobo; He, Li et al. (2011) Spatiotemporal control of small GTPases with light using the LOV domain. Methods Enzymol 497:393-407
Prasad, Mohit; Wang, Xiaobo; He, Li et al. (2011) Border cell migration: a model system for live imaging and genetic analysis of collective cell movement. Methods Mol Biol 769:277-86
Kim, Ji Hoon; Cho, Aeri; Yin, Hongyan et al. (2011) Psidin, a conserved protein that regulates protrusion dynamics and cell migration. Genes Dev 25:730-41
He, Li; Wang, Xiaobo; Tang, Ho Lam et al. (2010) Tissue elongation requires oscillating contractions of a basal actomyosin network. Nat Cell Biol 12:1133-42
Jang, Anna C-C; Chang, Yu-Chiuan; Bai, Jianwu et al. (2009) Border-cell migration requires integration of spatial and temporal signals by the BTB protein Abrupt. Nat Cell Biol 11:569-79
McDonald, Jocelyn A; Khodyakova, Anna; Aranjuez, George et al. (2008) PAR-1 kinase regulates epithelial detachment and directional protrusion of migrating border cells. Curr Biol 18:1659-67
Starz-Gaiano, Michelle; Melani, Mariana; Wang, Xiaobo et al. (2008) Feedback inhibition of Jak/STAT signaling by apontic is required to limit an invasive cell population. Dev Cell 14:726-38

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