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| Drosophila ovary subunit, called the egg chamber, labeled for microtubules (magenta) and actin (green). The group of border cells (arrow) separates from the epithelial follicle cells (magenta), migrates between cells called the nurse cells (green), until they finally reach the oocyte, where they stop. Ultimately, border cells form a structure called the micropyle, which is required for fertilization of the oocyte. |
We investigate how cellular movement is regulated within the three-dimensional environment of tissues. Cells move during normal processes, such as during embryonic development, wound healing and ordinary immune system function, whereas abnormal migration contributes to birth defects and tumor metastasis in cancer. Our lab studies a group of cells called border cells, which migrate as a cohesive unit during development of the model organism Drosophila melanogaster. We use Drosophila because of the variety of sophisticated genetic and molecular tools available that allow us to identify new genes that control movement of these cells. Furthermore, most of these genes have counterparts in humans, and the ultimate goal of the lab is to determine whether the genes we identify in Drosophila also regulate human cell migration in pathological contexts such as abnormal wound healing or metastatic cancer.
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| Live-cell imaging of border cell (BC) migration: series of micrographs taken from a 4-hour time-lapse movie. (Panels 1-2) Border cells (arrow, marked with Green Fluorescent Protein) separate/detach from the adjacent epithelial cells, which are unmarked in this egg chamber; (Panels 3-5) border cells migrate ~150 µm; (Panel 6) border cells stop migrating when they reach the oocyte. The egg chamber and oocyte are outlined for clarity; time in hours: minutes. |
We use a combination of live-cell imaging, forward and reverse genetics, immunofluorescence, microscopy, cell culture and molecular biology techniques in order to discover new molecular pathways that regulate border cell migration. Many proteins that regulate border cell migration, including the cytokine signaling proteins JAK-STAT, the Epidermal Growth Factor Receptor (EGFR), and the small GTPase Rac, also function in human cell migration and have been implicated in tumorigenesis and/or metastasis. However, in mammals it is often difficult and/or time-consuming to identify new molecular pathways that regulate cell migration in the context of the tissue microenvironment. Border cells represent an excellent, simple model for tumor invasion and metastasis in human cancer.
In a screen for mutants that regulate border cell migration, we recently identified mutant alleles of a gene called par-1 ( partioning defective gene 1 ) that caused frequent border cell migration defects (McDonald et al. 2008). Par-1 encodes a highly conserved serine-threonine kinase that has known roles in regulating cell polarity, Wnt signaling, and microtubule stability. Par-1 homologs in humans, called Mark1-4 (Microtubule Affinity Regulating Kinase), have been implicated in several cancers, although their precise roles and mechanisms are unknown. Our results indicate that Drosophila Par-1 regulates three distinct steps of border cell migration: separation/detachment of border cells from adjacent epithelial follicle cells at the beginning of the migratory process, directional protrusion, and protrusion morphology.
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Top, wild type border cells (arrow) reach the oocyte (dotted line). Bottom, par-1 mutant border cells (arrow) did not migrate. |
Border cell protrusions, which have similar characteristics to the lamellae and filopodia formed by vertebrate cells, help the cells sense their environment and provide pulling and traction forces for the cells to move forward. It is critical for protrusions to extend in the proper direction and to have the proper shape and tensile strength in order to prevent loss of cell motility. Currently, we are investigating the molecular mechanisms by which Par-1 regulates each of these steps, focusing on whether Par-1 modulates cell-cell adhesion, cytoskeletal, and/or signaling pathways. In addition, we recently performed a mutagenesis screen to identify new molecular players regulating border cell migration. Our efforts are focused on identifying and characterizing these mutated genes. Finally, in collaboration with the lab of Dr. Ganes Sen (Molecular Genetics), we are studying conserved developmental and cellular roles of double-stranded RNA-binding proteins.