Genetic regulation of collective cell migration
Cell migration is a characteristic feature of numerous biologically important processes such as embryo development, tissue homeostasis, wound healing, inflammation, and cancer metastasis. The migration of cells in groups, known as collective cell migration, is observed during embryogenesis and dissemination of some types of cancers. Many relevant aspects of collective cell migration remain unanswered: how is the migratory group selected from the larger population of cells from which they derive? How are the adhesive contacts among the members of the collective regulated during migration? What are the molecular mechanisms that cells use to migrate in groups? We have used the collective movements that occur during Drosophila oogenesis as a genetically tractable system to answer such questions.
The gene apontic was identified in a screen for genes that affect border cell migration. apontic mutant egg chambers contain 2-7 extra-migratory cells. We found apontic to be a transcriptional target of STAT and a negative regulator of STAT activity. Therefore, apontic is required to limit the migratory cell population by transforming a graded pattern of STAT activation into a step-wise cell fate decision.
Hindsight is a transcription factor required during morphogenetic changes during Drosophila embryogenesis. Anterior follicle cells mutant for hindsight failed to flatten and border cells and failed to migrate. hindsight regulates several adhesion proteins. Down-regulation of the hindsight human homolog RREB1 restricted migration of breast epithelial cells. Altogether, hindsight adjusts the levels of adhesion contacts among the members of a migratory group to allow morphogenesis while maintaining tissue integrity.
Border cells appear to undergo a partial epithelial to mesenchymal transition (EMT) as they migrate. We are investigating the role of snail, a regulator of EMT, during border cell migration. snail mutant border cells failed to initiate migration and remained within the follicular epithelium. snail over-expressing border cells also showed severe migration defects. Low levels of snail expression might therefore be required to induce a partial-EMT in the border cells and promote migration.
The genes studied in this Dissertation, fine-tune different and equally important aspects of collective migration: selection of the migratory population, regulation of adhesion strength and partial EMT.
0379: Cellular biology