Evidence for the mechanosensor function of filamin in tissue development

Abstract

Cells integrate mechanical properties of their surroundings to form multicellular, three-dimensional tissues of appropriate size and spatial organisation. Actin cytoskeleton-linked proteins such as talin, vinculin and filamin function as mechanosensors in cells, but it has yet to be tested whether the mechanosensitivity is important for their function in intact tissues. Here we tested, how filamin mechanosensing contributes to oogenesis in Drosophila. Mutations that require more or less force to open the mechanosensor region demonstrate that filamin mechanosensitivity is important for the maturation of actin-rich ring canals that are essential for Drosophila egg development. The open mutant was more tightly bound to the ring canal structure while the closed mutant dissociated more frequently. Thus, our results show that an appropriate level of mechanical sensitivity is required for filamins’ function and dynamics during Drosophila egg growth and support the structure-based model in which the opening and closing of the mechanosensor region regulates filamin binding to cellular components.

Filamin actin-binding and titin-binding fulfill distinct functions in Z-disc cohesion

“…Drosophila filamin is highly conserved with vertebrate filamins lacking only two Ig repeats in the rod 1 domain [10]. Cheerio recruits actin filaments to the ring canal and likely tethers the ring canal to the plasma membrane [18–20].…”

Differential regulation of twoFLNAtranscripts explains some of the phenotypic heterogeneity in the loss-of-function filaminopathies

“…FLNA plays diverse roles in the cell acting as a mechanical sensor (Huelsmann, Rintanen, Sethi, Brown, & Ylänne, 2016;Lad et al, 2007;Liu et al, 2015;Nakamura, Song, Hartwig, & Stossel, 2014), a regulator of the cytoskeleton, which influences cell shape and motility (Popowicz, Schleicher, Noegel, & Holak, 2006), and a scaffolding hub for transmission of biochemical signaling pathways, which facilitate organogenesis in multiple systems during embryonic development (Feng & Walsh, 2004;Robertson et al, 2003). As a cytoskeletal protein, FLNA crosslinks actin into either orthogonal networks or bundled stress fibers (Robertson, 2005;van der Flier & Sonnenberg, 2001) with the ratio of actin:filamin determining the relative stiffness of the cytoskeleton (Schmoller, Lieleg, & Bausch, 2009).…”

Harnessing the adaptive potential of mechanoresponsive proteins to overwhelm pancreatic cancer dissemination and invasion

“…Entire programs are upregulated to provide cells with added adaptability at specific time points as developing embryos and differentiating cells show increased expression of mechanoresponsive proteins during mechanically turbulent periods. For example, filamin's mechanoresponsiveness is required for maturation of actin-rich ring canals that interconnect the nurse cells and oocyte in developing Drosophila egg chambers 48 , and filamin B is upregulated in embryonic vascular endothelial cells 49 . Both α-actinin 1 and α-actinin 4 show temporally defined expression in developing zebrafish embryos, with both expressed in the notochord and α-actinin 4 also expressed in the developing gut 50 .…”