Tipping the scales: how Drosophila border cells balance cellular requirements for a successful collective migration

Abstract

Throughout the life of an organism, collective migrations underlie development and homeostasis, including wound healing and cancer metastasis. Drosophila border cells form a small collective and undergo a dynamic migration during normal egg development. During migration, the downstream activity of several signaling pathways directs collective behavior, including cell movements and adhesion remodeling, while maintaining cell-cell adhesion between border cells and responding to the dense surrounding environment. Eventually, the border cells cease migration and return to a stationary, epithelial fate. To understand how border cells balance these developmental roles, we performed RNA sequencing on border cells isolated at pre-, mid-, and late migration stages. Downstream gene ontology and protein-protein interaction network analyses identified differentially expressed genes expected to function in collective migration, but also revealed temporal regulation of ribosome biogenesis genes. Expression, interaction, and functional data obtained in these experiments can be used to identify new candidate gene groups with potential molecular roles in border cell migration. Surprisingly, activating transcription factor 4 (ATF4), a downstream effector of the integrated stress response (ISR), was among the most highly expressed genes in border cells during their migration. ATF4 overexpression and knockdown both resulted in migration defects in the border cell cluster, including significant changes in border cell number and overall cluster shape. Finally, we demonstrate that ATF4 overexpression prevents border cell motility, restricting border cells with elevated levels of ATF4 to the rear of the cluster during migration. Our transcriptome analysis and functional studies identified dynamic expression and a requirement for migration-related genes, but also ribosome biogenesis and stress response genes. Together, our data indicate a balance in these cellular requirements in Drosophila border cells to promote their collective migration.