601C Poster - 08. Patterning, morphogenesis and organogenesis
Saturday April 09, 1:30 PM - 3:30 PM

ArfGAP1 regulates collective cell migration in vivo.


Authors:
Alison Boutet 1,2; Carlos Zeledon 1,2; Xiaojuan Sun 3; Gregory Emery 1,2

Affiliations:
1) Institut de recherche en immunologie et en cancérologie, IRIC, Montréal, Canada; 2) Université de Montréal, Montréal, Canada; 3) School of Basic Medical Sciences, Henan University, Kaifeng, China

Keywords:
p. cell migration; c. endocytosis

Introduction: Collective cell migration plays important roles in morphogenesis and embryonic development and is a main feature of the formation of metastases in several cancers. Unlike single cell migration, collective cell migration is characterized by cell-cell adhesion and cell-cell communication. We have previously demonstrated that vesicular trafficking plays a critical role in cell guidance and cell-cell communication during collective cell migration. A recent screen aimed at identifying new regulators of vesicular trafficking involved in collective migration identified ArfGAP1 as a regulator of border cell migration in the Drosophila ovary.

Methods and Results: Between stages 9 and 10 of the Drosophila egg chamber development, the so-called border cells form a cluster that is attracted by the oocyte through the secretion of ligands to receptor tyrosine kinases (RTKs). We found that the depletion of ArfGAP1 specifically in border cells induces migration defects. Indeed, clusters devoid of ArfGAP1 are able to initiate their migration, but loose directionality. Investigating the cause of this phenotype by analyzing various determinants of border cell migration, we found that the depletion of ArfGAP1 reduces the level of active RTKs at the plasma membrane as they accumulate in late endosomal compartments. Looking further in the degradative pathway, our results indicate an increase of active RTKs inside late endosomes, combined with an increase in Rab7 signal and lysosomes in border cells depleted of ArfGAP1. Our results suggest that ArfGAP1 is necessary for the proper sorting of active RTKs in endosomes to maintain RTKs at the plasma membrane and allow directionality. Moreover, rescue experiments and genetic interactions revealed that the role of ArfGAP1 in border cell migration is dependant of its GAP activity and could act through Hrs and Lrrk, two proteins involved in multivesicular body formation and RTKs degradation.

Conclusion and Relevance: We identified ArfGAP1 as a new regulator of border cell migration that might acting through vesicular trafficking to maintain of active receptor tyrosine kinases at the plasma membrane. This study could potentially reveal a new important mechanism in collective cell migration, and by extent in cancer dissemination.