Research interests: cell migration

In many instances, cells must migrate long distances to fulfill their destiny. For example, numerous cell types in developing embryos are born some distance away from where they will be required in the fully formed organism. In the case of an injury, immune cells travel to the site to fight infections, and skin cells move to repair a wound. These migrations occur with great precision in time and space such that few cells get lost. As someone who needs an alarm clock to wake up and a map to get around Baltimore, I think this is amazing. How are cells selected to become motile cells, and detach from their neighbors that stay behind? How do they know when it is time to go? What signals guide their movements through complex tissues? How do they “put on the brakes” when it is time to stop? These questions are of fundamental interest to developmental biologists, and have major implications in medicine as well. Defects in cell migration can lead to birth defects in humans. In addition, cancers are most lethal when they become metastatic, acquiring the ability to leave a tumor and spread and hide throughout the body.

I am currently using Drosophila melanogaster as a model system for addressing unanswered questions in cell movement. The vast array of genetic tools in fruit flies, as well as their fast generation time and small size, makes them ideal for these studies. Also, it has been shown that genes involved in cell movements in flies also play roles in cell migration and cancer metastasis in vertebrates (reviewed in Jang et al 2007; Naora and Montell, 2005).

Specifying a migratory cell population

The current focus of the lab is on the movement of the border cells, a cluster of cells in the ovary that detach from an epithelial cell layer and undergo a stereotyped movement between germ line cells as the egg develops (schematized in Figure 1). Border cells ultimately form a structure that allows the egg to be fertilized. We have found a three-component genetic circuit of transcription factors that is responsible for specifying the correct number of motile cells. Loss or overexpression of any of the genes –apontic, stat, or slow border cells – causes too many cells to become motile, and thereby disrupts cell migration (see Figure 2 for an example of an apontic (apt) loss of function phenotype). We are interested in the downstream mechanisms responsible for this defect; in particular, what molecules cause the cells to remain attached to their neighbors when they should disconnect? Regulation of cell adhesion molecules such as Cadherins are likely to be involved in this detachment step, and this is being investigated. apontic and stat are also required for morphogenesis of tube formation of the tracheal system during fly embryogenesis, and we are interested in further characterizing their interactions and functions during this migratory process.

Steroid hormone control of timing

Border cells are specified significantly before they begin to migrate. As is the case for humans, steroid hormones in insects are responsible for coordinating developmental events over time, and it has been shown that a steroid hormone signal gives the border cells a cue to go now. There is only one steroid hormone in flies, called ecdysone. Like other hormones, ecdysone binds to a receptor, which translocates to the nucleus to initiate a cascade of transcription. Ecdysone receptor acts in a complex with several required co-factors including Ultraspiracle, the fly homolog to human RXR, and Taiman, which shares homology with the breast cancer oncogene amplified in breast cancer 1 (AIB1/SRC-3). All of these genes are required for border cell migration (Bai, 2000). We are very interested in the downstream signals that instruct border cells to “go” and have completed microarray experiments to identify target genes. Loss of function and gain of function studies are underway to identify critical targets and to determine which genes are required for cell migration. Required genes may likely play a role in breast and ovarian cancer metastases.

References:

1 Jang AC, Starz-Gaiano M, Montell DJ. Modeling migration and metastasis in Drosophila. J Mammary Gland Biol Neoplasia. 2007 Sep;12(2-3):103-14.

2 Naora H, Montell DJ. Ovarian cancer metastasis: integrating insights from disparate model organisms. Nat Rev Cancer. 2005 May;5(5):355-66.

3 Bai J, Uehara Y, Montell DJ. Regulation of invasive cell behavior by taiman, a Drosophila protein related to AIB1, a steroid receptor coactivator amplified in breast cancer. Cell. 2000 Dec 22;103(7):1047-58.