The Hippo Pathway Controls Border Cell Migration Through Distinct Mechanisms in Outer Border Cells and Polar Cells of the Drosophila Ovary

Abstract

The Hippo pathway is a key signaling cascade in controlling organ size. The core components of this pathway are two kinases, Hippo (Hpo) and Warts (Wts), and a transcriptional coactivator, Yorkie (Yki). Yes-associated protein (YAP, a Yki homolog in mammals) promotes epithelial-mesenchymal transition and cell migration in vitro. Here, we use border cells in the Drosophila ovary as a model to study Hippo pathway functions in cell migration in vivo. During oogenesis, polar cells secrete Unpaired (Upd), which activates JAK/STAT signaling of neighboring cells and specifies them into outer border cells. The outer border cells form a cluster with polar cells and undergo migration. We find that hpo and wts are required for migration of the border cell cluster. In outer border cells, overexpression of hpo disrupts polarization of the actin cytoskeleton and attenuates migration. In polar cells, knockdown of hpo and wts or overexpression of yki impairs border cell induction and disrupts migration. These manipulations in polar cells reduce JAK/STAT activity in outer border cells. Expression of upd-lacZ is increased and decreased in yki and hpo mutant polar cells, respectively. Furthermore, forced expression of upd in polar cells rescues defects of border cell induction and migration caused by wts knockdown. These results suggest that Yki negatively regulates border cell induction by inhibiting JAK/STAT signaling. Together, our data elucidate two distinct mechanisms of the Hippo pathway in controlling border cell migration: (1) in outer border cells, it regulates polarized distribution of the actin cytoskeleton; (2) in polar cells, it regulates upd expression to control border cell induction and migration.

Hippo signaling promotes JNK-dependent cell migration

“…Interestingly, despite that Yki overexpression phenocopies wts knockdown-induced migratory defect (31), we found inhibition of Yki activity under upd promoter is not sufficient to accelerate border cell migration (Fig. S5 A and B), which is consistent with a previous study (31).…”

“…Consistent with our data, both TIA1 and YAP have nucleo-cytoplasmic shuttling ability (7,50,51). Interestingly, recent studies found that hpo and wts are both required for border cell migration during oogenesis (31,32), highlighting the importance of cell migration promoting roles of the Hippo pathway. On the basis of that finding, our data further demonstrate that JNK acts downstream of Hippo pathway in inducing normal border cell migration (Fig.…”

“…Stage-10 egg chambers were selected and analyzed as previously described (31). As an index for migration, stage-10 egg chambers were categorized based on the location of the border cell cluster as depicted in Fig.…”

“…Next, to investigate the physiological role of Hippo-JNK cross-talk in regulating cell migration, we turn to oogenesis, a developmental process where both JNK and Hippo are required for correct border cell migration (30)(31)(32). During normal development, the border cell cluster arrives at the nurse cell-oocyte boundary by stage 10 ( Fig.…”

Yorkie regulates epidermal wound healing in Drosophila larvae independently of cell proliferation and apoptosis

“…In mammalian cell culture, YAP/TAZ activity is also regulated by tension of the actin cytoskeleton (Dupont et al, 2011). These effects may be bidirectional in some cases; the Hippo pathway also regulates the actin cytoskeleton in Drosophila imaginal discs (Fernández et al, 2011; Lin et al, 2014). Other studies suggest that overexpression of Yorkie can directly influence actin levels at wing hair initiation sites (Fang and Adler, 2010).…”