Fidgetin-like 2: A novel microtubule-based regulator of wound healing and vasculogenesis
Charafeddine, Rabab Ali
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The microtubule cytoskeleton has been implicated in regulating cell migration in vitro through the functions of different molecules that affect the stability and organization of the polymer. However, whether this involvement still holds in animal models has not been extensively investigated. Here we present Fidgetin-like 2 (FL2), an uncharacterized family member of the microtubule severing enzymes that regulates cell migration both in vitro and in murine cutaneous wound healing models. Knockdown of FL2 significantly enhanced the rate of cell migration as well as cell directionality in wound-closure assays. Concurrently, cells exhibited an expansion in total microtubule polymer mass as well as bundling at their leading edge. Microtubule plus-tip tracker EB 1 further revealed an upsurge in microtubule plus-ends and an increase in EB 1 comet length. Consistent with FL2's speckle like localization at the cell cortex, FL2 depletion enlarged the size and number of focal adhesions. We were able to translate these findings in vivo both in excision and burn wounds using nanoparticle encapsulated siRNA (NPsi) to topically and specifically deplete FL2 from the wound site. FL2 NPsi treatment of wounds expedited wound closure and improved the quality of wound healing. In a separate pilot project, FL2 knockdown in murine embryonic ventricle expiants as well as human umbilical vein cells enhanced vessel formation and altered its composition. Remarkably, FL2 depletion changed the expression levels of several vascular markers and upstream regulators in the expiants. These data introduce FL2 as a novel cell migration regulator in repair and development as well as a potential therapeutic target.