GMF Promotes Leading-Edge Dynamics and Collective Cell Migration In Vivo

Abstract

SUMMARY Lamellipodia are dynamic actin-rich cellular extensions, which drive advancement of the leading edge during cell migration [1–3]. Lamellipodia undergo periodic extension/retraction cycles [4–8], but the molecular mechanisms underlying these dynamics and their role in cell migration have remained obscure. We show that gliamaturation factor (GMF), which is an Arp2/3 complex inhibitor and actin filament debranching factor [9, 10], regulates lamellipodial protrusion dynamics in living cells. In cultured S2R+ cells, GMF silencing resulted in an increase in the width of lamellipodial actin filament arrays. Importantly, live-imaging of mutant Drosophila egg chambers revealed that the dynamics of actin-rich protrusions in migrating border cells are diminished in the absence of GMF. Consequently, velocity of border cell clusters undergoing guided migration was reduced in GMF mutant flies. Furthermore, genetic studies demonstrated that GMF cooperates with the Drosophila homologue of Aip1 (flare) in promoting disassembly of Arp2/3-nucleated actin filament networks and driving border cell migration. These data suggest that GMF functions in vivo to promote the disassembly of Arp2/3-nucleated actin filament arrays, making an important contribution to cell migration within a three-dimensional tissue environment.

The roles and regulation of the actin cytoskeleton, intermediate filaments and microtubules in smooth muscle cell migration

“…Glia maturation factor-γ (GMF-γ) is a 17 kDa member of the ADF/cofilin family that is capable of inducing actin depolymerization and debranching [28]. GMF-γ is able to bind to the Arp2/3 complex at the junction of mother filaments and daughter filaments, which induces debranching of the actin meshwork [28, 29]. Subsequently, debranched filaments are severed by gelsolin and depolymerized by ADF/cofilin, which eventually generate more G-actin pools for subsequent rounds of actin filament polymerization and branching [4, 28, 29].…”

Cellular functions of the ADF/cofilin family at a glance

“…However, although cofilin debranching activity has been studied and does occur, another cofilin-like molecule termed glia maturation factor (GMF, of which there are different isoforms) appears to be more specific for the Arp2/3 complex branches and is more efficient than cofilin in mediating debranching (Haynes et al, 2015;Poukkula et al, 2014;Ydenberg et al, 2013).…”

Structural Basis of Arp2/3 Complex Inhibition by GMF, Coronin, and Arpin

“…However, rather than binding to actin like ADF/cofilin, GMF binds directly to Arp2/3 complex via interactions with the Arp2 and p40/ARPC1 subunits [12–14]. Through these interactions, GMF inhibits actin nucleation by Arp2/3 complex, and catalyzes the dissociation of daughter filaments from mother filaments, i.e., debranching [13, 32, 33]. A co-crystal structure of GMF-bound Arp2/3 complex revealed that one of the GMF binding sites to be located on the Arp2 and ARPC1/p40 subunits [14].…”