title: Investigating circular dorsal ruffles through varying substrate stiffness and mathematical modeling.
abstract: Circular dorsal ruffles (CDRs) are transient actin-rich ringlike structures that form on the dorsal surface of growth-factor stimulated cells. However, the dynamics and mechanism of formation of CDRs are still unknown. It has been observed that CDR formation leads to stress fibers disappearing near the CDRs. Because stress fiber formation can be modified by substrate stiffness, we examined the effect of substrate stiffness on CDR formation by seeding NIH 3T3 fibroblasts on glass and polydimethylsiloxane substrates of varying stiffnesses from 20 kPa to 1800 kPa. We found that increasing substrate stiffness increased the lifetime of the CDRs. We developed a mathematical model of the signaling pathways involved in CDR formation to provide insight into this lifetime and size dependence that is linked to substrate stiffness via Rac-Rho antagonism. From the model, increasing stiffness raised mDia1-nucleated stress fiber formation due to Rho activation. The increased stress fibers present increased replenishment of the G-actin pool, therefore prolonging Arp2/3-nucleated CDR formation due to Rac activation. Negative feedback by WAVE-related RacGAP on Rac explained how CDR actin propagates as an excitable wave, much like wave propagation in other excitable medium, e.g., nerve signal transmission.
authors: Mechanical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.
authors: Yukai
authors: Y
authors: Zeng
authors: Tanny
authors: T
authors: Lai
authors: Cheng Gee
authors: CG
authors: Koh
authors: Philip R
authors: PR
authors: LeDuc
authors: K-H
authors: KH
authors: Chiam
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D022081:Cell Surface Extensions / Q000187:drug effects*; D003198:Computer Simulation; D004129:Dimethylpolysiloxanes / Q000494:pharmacology; D025461:Feedback, Physiological / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D022502:Stress Fibers / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000199:Actins; D004129:Dimethylpolysiloxanes; D010982:Platelet-Derived Growth Factor; D017479:Receptors, Platelet-Derived Growth Factor; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins