Guidance receptor promotes the asymmetric distribution of exocyst and recycling endosome during collective cell migration

Abstract

During collective migration, guidance receptors signal downstream to result in a polarized distribution of molecules, including cytoskeletal regulators and guidance receptors themselves, in response to an extracellular gradient of chemotactic factors. However, the underlying mechanism of asymmetry generation in the context of the migration of a group of cells is not well understood. Using border cells in the Drosophila ovary as a model system for collective migration, we found that the receptor tyrosine kinase (RTK) PDGF/VEGF receptor (PVR) is required for a polarized distribution of recycling endosome and exocyst in the leading cells of the border cell cluster. Interestingly, PVR signaled through the small GTPase Rac to positively affect the levels of Rab11-labeled recycling endosomes, probably in an F-actindependent manner. Conversely, the exocyst complex component Sec3 was required for the asymmetric localization of RTK activity and F-actin, similar to that previously reported for the function of Rab11. Together, these results suggested a positive-feedback loop in border cells, in which RTKs such as PVR act to induce a higher level of vesicle recycling and tethering activity in the leading cells, which in turn enables RTK activity to be distributed in a more polarized fashion at the front. We also provided evidence that E-cadherin, the major adhesion molecule for border cell migration, is a specific cargo in the Rab11-labeled recycling endosomes and that Sec3 is required for the delivery of the E-cadherin-containing vesicles to the membrane.

PIP kinases define PI4,5P2 signaling specificity by association with effectors

“…This would ensure the efficient polarized recruitment and delivery of transmembrane proteins and signaling molecules that are required for nascent adhesion formation in migrating cells. Consistently, knockdown of PIPKIγ and the exocyst complex profoundly affect leading edge formation, polarized recruitment of integrins and cell migration [38, 142, 147, 148] (Figure 2). The spatial targeting of integrins is regulated by vesicle associated PIPKIγi2.…”

FGF control of E-cadherin targeting in the Drosophila midgut impacts on primordial germ cell motility

“…This would be an interesting avenue of research. It has been reported, in migratory border cells, that Pvr signaling, through the small GTPase Rac, increases recycling endosome levels (Wan et al, 2013), leading presumably to increased E-cadherin transport to adherens junctions. By contrast, in tracheal cells, Rac functions to maintain lower E-cadherin levels and it has been suggested that BtlBnl signaling activates Rac as these two signaling pathways genetically interact (Chihara et al, 2003).…”

“…Hence, blocking FGF signaling could reduce cytoskeleton dynamics and indirectly block or diminish Rab11-exocyst trafficking of E-cadherin. This mechanism could also have a contribution from Rac signaling, given that all these regulators are in place for regulation of endosome levels in border cells (Wan et al, 2013). It would be of great interest to explore the molecular mechanism by which FGF modulates trafficking of zygotic E-cadherin.…”

Exocyst Regulates Drosophila Border Cell Migration and Wing Development

“…We have identified loss of function of Drosophila sec3 causes border cell migration defects in a previous study (3). Since the expression pattern of Sec3 in Drosophila has not been reported yet, we wanted to examine the protein localization of Sec3 and determine whether it shows a polarized localization in cells as other exocyst component having been reported.…”