mDia1 coordinates mast cell migration and secretion through its actin nucleating activity

Abstract Background Actin remodelling is a key regulator of mast cell (MC) migration and secretion. However, the precise mechanism underlying the coordination of these processes has remained obscure. Objective We sought to characterize the actin rearrangements that occur during MC secretion or chemotactic migration and identify the underlying mechanism of their coordination. Methods We analyzed by high resolution microscopy the dynamics of actin rearrangements in MCs triggered to migration by IL8 or PGE2, or to FceRI-stimulated secretion. Results We show that a major feature of the actin skeleton in MCs stimulated to migration is the buildup of pericentral actin clusters that prevent cell flattening and converge the secretory granules (SGs) in the cell center. This migratory phenotype is replaced upon encounter of an IgE crosslinking antigen, that stimulates secretion, by a secretory phenotype characterized by cell flattening, reduction of actin mesh density, ruffling of the cortical actin and mobilization of the SGs. Further, we show that knockdown of diaphanous-related formin mDia1 inhibits chemotactic migration and its typical actin rearrangements, while expression of an active mDia1 mutant recapitulates the migratory actin phenotype and enhances cell migration, while inhibiting FceRI-triggered secretion. However, mice deficient in mDia1 appear to have normal numbers of MCs in various organs at baseline. Conclusion Our results demonstrate a unique role of actin rearrangements in clustering the SGs and inhibiting their secretion during MC migration. We identify mDia1 as a novel regulator of MC responses that coordinates MC chemotaxis and secretion through its actin nucleating activity.