20 research outputs found
Actin Migration Driven by Directional Assembly and Disassembly of Membrane-Anchored Actin Filaments
Get PDFActin and actin-associated proteins migrate within various cell types. To uncover the mechanism of their migration, we analyzed actin waves, which translocate actin and actin-associated proteins along neuronal axons toward the growth cones. We found that arrays of actin filaments constituting waves undergo directional assembly and disassembly, with their polymerizing ends oriented toward the axonal tip, and that the lateral side of the filaments is mechanically anchored to the adhesive substrate. A combination of live-cell imaging, molecular manipulation, force measurement, and mathematical modeling revealed that wave migration is driven by directional assembly and disassembly of actin filaments and their anchorage to the substrate. Actin-associated proteins co-migrate with actin filaments by interacting with them. Furthermore, blocking this migration, by creating an adhesion-free gap along the axon, disrupts axonal protrusion. Our findings identify a molecular mechanism that translocates actin and associated proteins toward the cell’s leading edge, thereby promoting directional cell motility.journal articl
Hedgehog Signal and Genetic Disorders
Get PDFThe hedgehog (Hh) family comprises sonic hedgehog (Shh), Indian hedgehog (Ihh), and desert hedgehog (Dhh), which are versatile signaling molecules involved in a wide spectrum of biological events including cell differentiation, proliferation, and survival; establishment of the vertebrate body plan; and aging. These molecules play critical roles from embryogenesis to adult stages; therefore, alterations such as abnormal expression or mutations of the genes involved and their downstream factors cause a variety of genetic disorders at different stages. The Hh family involves many signaling mediators and functions through complex mechanisms, and achieving a comprehensive understanding of the entire signaling system is challenging. This review discusses the signaling mediators of the Hh pathway and their functions at the cellular and organismal levels. We first focus on the roles of Hh signaling mediators in signal transduction at the cellular level and the networks formed by these factors. Then, we analyze the spatiotemporal pattern of expression of Hh pathway molecules in tissues and organs, and describe the phenotypes of mutant mice. Finally, we discuss the genetic disorders caused by malfunction of Hh signaling-related molecules in humans.journal articl
Systems biology of symmetry breaking during neuronal polarity formation
Get PDFPolarization, in which a single axon and multiple dendrites are formed, is crucial for neuronal functions, and symmetry breaking is the initial step of this process. Accumulating studies have revealed a number of molecules that act asymmetrically in neurons, and thereby regulate neuronal polarity. Thus, one of the major goals of current research is to understand how asymmetric signals are generated during the symmetry-breaking step. Current models of neuronal symmetry breaking generally involve local activation for induction of axon outgrowth and global inhibition to suppress formation of multiple axons and can be categorized into one-takes-all and activator-inhibitor models. Both types of model incorporate a positive feedback loop to execute local activation, but differ in the manner of global inhibition. Quantitative experimentation combined with computational modeling is a powerful strategy in systems biology, and analyses in this direction have begun to yield a more profound understanding of how neurons break their symmetry during polarity formation.journal articl
Conversion of a Signal into Forces for Axon Outgrowth through Pak1-Mediated Shootin1 Phosphorylation
Get PDFSoluble guidance cues can direct cellular protrusion and migration by modulating adhesion and cytoskeletal dynamics. Actin filaments (F-actins) polymerize at the leading edge of motile cells and depolymerize proximally [1 and 2]; this, together with myosin II activity, induces retrograde flow of F-actins [3, 4 and 5]. It has been proposed that the traction forces underlying cellular motility may be regulated by the modulation of coupling efficiency between F-actin flow and the extracellular substrate via “clutch” molecules [6, 7, 8, 9 and 10]. However, how cell signaling controls the coupling efficiency remains unknown. Shootin1 functions as a linker molecule that couples F-actin retrograde flow and the substrate at neuronal growth cones to promote axon outgrowth [11]. Here we show that shootin1 is located at a critical interface, transducing a chemical signal into traction forces for axon outgrowth. We found that a chemoattractant, netrin-1, positively regulates traction forces at axonal growth cones via Pak1-mediated shootin1 phosphorylation. This phosphorylation enhanced the interaction between shootin1 and F-actin retrograde flow, thereby promoting F-actin-substrate coupling, force generation, and concomitant filopodium extension and axon outgrowth. These results suggest that dynamic actin-substrate coupling can transduce chemical signals into mechanical forces to control cellular motility and provide a molecular-level description of how this transduction may occur.journal articl
