Formins in development: Orchestrating body plan origami

Abstract

Formins, proteins defined by the presence of an FH2 domain and their ability to nucleate linear F-actin de novo, play a key role in the regulation of the cytoskeleton. Initially thought to primarily regulate actin, recent studies have highlighted a role for formins in the regulation of microtubule dynamics, and most recently have uncovered the ability of some formins to coordinate the organization of both the microtubule and actin cytoskeletons. While biochemical analyses of this family of proteins have yielded many insights into how formins regulate diverse cytoskeletal reorganizations, we are only beginning to appreciate how and when these functional properties are relevant to biological processes in a developmental or organismal context. Developmental genetic studies in fungi, Dictyostelium, vertebrates, plants and other model organisms have revealed conserved roles for formins in cell polarity, actin cable assembly and cytokinesis. However, roles have also been discovered for formins that are specific to particular organisms. Thus, formins perform both global and specific functions, with some of these roles concurring with previous biochemical data and others exposing new properties of formins. While not all family members have been examined across all organisms, the analyses to date highlight the significance of the flexibility within the formin family to regulate a broad spectrum of diverse cytoskeletal processes during development.

The actin cross-linker Filamin/Cheerio mediates tumor malignancy downstream of JNK signaling

“…1B). A role for diaphanous-like formins in cancer progression is supported by previous studies in mammalian models (Nürnberg et al, 2011), and effects of Drosophila Dia on cell motility (Liu et al, 2010), and regulation of imaginal disc growth (Sansores-Garcia et al, 2011) (Fig. 1C).…”

The novel formin FMNL3 is a cytoskeletal regulator of angiogenesis.

“…This is consistent with a role for FMNL3 in EC elongation, as the processes of vasculogenesis are morphologically distinct to those of angiogenesis and do not require the same polarised elongations (Carmeliet, 2000). Interestingly, although FMNL3 is highly conserved between humans and fish (72% identity), it is absent from Drosophila, which do not carry out angiogenesis and have a single, distantly related FMNL-like protein (Liu et al, 2010). Ciona, which sit at the bottom of the chordate clade, also lack the gene encoding FMNL3 (data not shown).…”

Dilated Cardiomyopathy-Associated <i>FHOD3</i> Variant Impairs the Ability to Induce Activation of Transcription Factor Serum Response Factor

“…5 Cooperation between the FH1 and FH2 domains regulates the formation of straight actin filaments, 6,7 thereby modulating diverse cytoskeletal reorganization during development of the heart. 8, 9 We have demonstrated that Fhod3 knockout mice display abnormal maturation of muscle fibers in the heart, resulting in embryonic lethality with ventricular hypokinesia. 10 In addition, transgenic mice expressing a mutant FHOD3 protein with Ile1127Ala (I1127A) substitution in the FH2 domain, which is defective in actin-assembling activity, exhibits phenotypic changes similar to DCM.…”