The overall interest of my laboratory is to understand how cell migration is regulated within the normal three-dimensional environment of tissues. Cells move during normal physiological processes, such as during embryonic development, wound healing and ordinary immune system function, whereas abnormal migration contributes to birth defects, tumor metastasis in cancer, failure of wounds to heal, and other disease pathologies. Therefore, it is of fundamental medical importance to identify the genetic, cellular, and molecular mechanisms that control cell movement.
My laboratory studies cells that migrate during development of the model organism Drosophila melanogaster, because of the variety of sophisticated genetic and molecular tools that allow us to identify new genes that control movement of these cells. Many of these genes have counterparts in humans, and the goal of the lab is to determine whether the genes identified in Drosophila also regulate human cell migration in pathological contexts.
We recently identified mutations in par-1 (partitioning defective-1), whose loss disrupts cell migration. Par-1 is a highly conserved serine-threonine kinase whose human homologs are implicated in several cancers, although their precise roles are unknown. We demonstrated that Par-1 regulates detachment of the migrating cells from a polarized epithelium and are currently characterizing how it functions in this process. In addition, we have identified several new molecular targets of Par-1, and are investigating their roles in regulating cell migration.
Cell movement is critical for normal development of the embryo and for adult health, but when unrestrained contributes to birth defects, abnormal wound closure, and tumor metastasis in cancer. Our research primarily uses a simple model of cell migration to discover new genes and molecular pathways that control how cells leave epithelia to move. Results from our studies are an important step towards the identification of new therapies to limit migration of cancer cells or to stimulate migration in wound healing.
Geisbrecht ER, Sawant K, Su Y, Liu ZC, Silver DL, Burtscher A, Wang X, Zhu AJ, McDonald JA. (2013). Genetic Interaction Screens Identify a Role for Hedgehog Signaling in Drosophila Border Cell Migration. Developmental Dynamics 242: 414-31.
Aranjuez G, Kudlaty E, Longworth MS, McDonald JA. (2012). On the role of PDZ domain-encoding genes in Drosophila border cell migration. G3: Genes/ Genomes/ Genetics 2: 1379-1391.
Majumder P, Aranjuez G, Amick J, McDonald JA. (2012). Par-1 Controls Myosin-II Activity Through Myosin Phosphatase To Regulate Border Cell Migration. Current Biology 22: 363-372.
McDonald JA*, Khodyakova A, Aranjuez G, Dudley C, Montell DJ* (2008). The Par-1 serine/threonine kinase regulates epithelial detachment and directional protrusion of migrating border cells. Current Biology 18: 1659-1667.
McDonald JA*,**, Pinheiro EM*, Kadlec L, Schupbach T, Montell DJ* (2006). Multiple EGFR ligands participate in guiding migrating border cells. Developmental Biology 296: 94-106.
**Co-First Authors; *Corresponding Authors.