title: Cofilin Regulates Nuclear Architecture through a Myosin-II Dependent Mechanotransduction Module.
abstract: Structural features of the nucleus including shape, size and deformability impact its function affecting normal cellular processes such as cell differentiation and pathological conditions such as tumor cell migration. Despite the fact that abnormal nuclear morphology has long been a defining characteristic for diseases such as cancer relatively little is known about the mechanisms that control normal nuclear architecture. Mounting evidence suggests close coupling between F-actin cytoskeletal organization and nuclear morphology however, mechanisms regulating this coupling are lacking. Here we identify that Cofilin/ADF-family F-actin remodeling proteins are essential for normal nuclear structure in different cell types. siRNA mediated silencing of Cofilin/ADF provokes striking nuclear defects including aberrant shapes, nuclear lamina disruption and reductions to peripheral heterochromatin. We provide evidence that these anomalies are primarily due to Rho kinase (ROCK) controlled excessive contractile myosin-II activity and not to elevated F-actin polymerization. Furthermore, we demonstrate a requirement for nuclear envelope LINC (linker of nucleoskeleton and cytoskeleton) complex proteins together with lamin A/C for nuclear aberrations induced by Cofilin/ADF loss. Our study elucidates a pivotal regulatory mechanism responsible for normal nuclear structure and which is expected to fundamentally influence nuclear function.
authors.affiliation: Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, 80523, USA.
authors.forename: O'Neil
authors.initials: O
authors.lastname: Wiggan
authors.affiliation: School of Biomedical Engineering, Colorado State University, Fort Collins, CO, 80523, USA.
authors.forename: Bryce
authors.initials: B
authors.lastname: Schroder
authors.affiliation: School of Biomedical Engineering, Colorado State University, Fort Collins, CO, 80523, USA.|Department of Electrical and Computer Engineering, Colorado State University, Fort Collins, CO, 80523, USA.
authors.forename: Diego
authors.initials: D
authors.lastname: Krapf
authors.affiliation: Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, 80523, USA.|School of Biomedical Engineering, Colorado State University, Fort Collins, CO, 80523, USA.|Molecular Cellular and Integrative Neuroscience, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Bamburg
authors.affiliation: Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, 80523, USA.
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: DeLuca
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D053144:Cell Nucleus Shape; D006801:Humans; D040542:Mechanotransduction, Cellular; D024462:Myosin Type II / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D051339:Actin Depolymerizing Factors; D054460:rho-Associated Kinases; D024462:Myosin Type II