Research Article: Microtubules Regulate Migratory Polarity through Rho/ROCK Signaling in T Cells

Date Published: January 19, 2010

Publisher: Public Library of Science

Author(s): Aya Takesono, Sarah J. Heasman, Beata Wojciak-Stothard, Ritu Garg, Anne J. Ridley, Joshua Z. Rappoport.

Abstract: Migrating leukocytes normally have a polarized morphology with an actin-rich lamellipodium at the front and a uropod at the rear. Microtubules (MTs) are required for persistent migration and chemotaxis, but how they affect cell polarity is not known.

Partial Text: Cell migration is essential for the recruitment of T cells to and circulation within lymphoid organs, where they encounter antigen-presenting dendritic cells, and in tissues during immune surveillance, immune responses and inflammation. Migrating T cells are normally morphologically polarized with spatially distinct front (lamellipodium) and rear (uropod) structures, and migrate by extending the lamellipodium forwards and retracting the uropod [1]–[3]. In lymph nodes in vivo, T cells migrate rapidly and for many hours until they encounter antigen [4]. In vitro, T cells polarize spontaneously, for example on the integrin ligand ICAM-1 [3], and this requires activation of the integrin LFA-1 [5]. Similarly, neutrophils polarize and migrate in a uniform concentration of chemokine [6], [7], a process that has been termed “self-organizing polarity” [8], [9].

MT depolymerization has been shown to reduce directional migration in several cell types including human neutrophils and zebrafish macrophages [19], [21], [56]. Here, we show that MT depolymerization converts T cells from a lamellipodial/uropod migratory phenotype to a blebbing migratory phenotype, correlating with increased RhoA/ROCK activity. ROCK inhibitors prevent blebbing and restore lamellipodial/uropod polarity to nocodazole-treated cells. In addition, we have found that ROCK inhibitors and the myosin inhibitor blebbistatin protect MTs against depolymerization. Our results support a model where RhoA/ROCK signaling contributes to T cell polarization and migration by regulating both contractility and MT stability (Figure 10).



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