02.24.10Lecture 17 - Cell motilityWednesday, February 24, 2010The Range of Cell Movement•Velocities of moving cells span more than 4 orders of magnitude• Each cell has evolved the speed and mechanism of its migration to match:•Developmental programs•The cell’s unique energy requirements•The way the cell acquires nutrients• The direction of cell migration is usually not random...Wednesday, February 24, 2010“-taxis” -Cell movement according to an environmental cue•Can be an attracting or repelling signal• Kinds of signals• Chemotaxis - soluble factor (molecule or protein)• Haptotaxis - same as chemotaxis, but the signal is immobilize on a surface• Durotaxis - rigidity of the cell’s substrateWednesday, February 24, 2010“-Taxis”, a form of cell signaling1. Reception of signal2. Transduction of signal3. Cellular responseCell motility towards or away from the signalWednesday, February 24, 2010Cellular locomotion is an essential part of life for many organismsSingle celled protozoa - Dictyostelium discoideumhttp://www.youtube.com/watch?v=VWGA7kIeE0QWednesday, February 24, 2010Cellular locomotion is an essential part of life for many organismsSingle celled protozoa - Dictyostelium discoideumhttp://www.youtube.com/watch?v=VWGA7kIeE0QMahadeo and Parent, 2006Wednesday, February 24, 2010Embryonic development in animalsMovements of autonomous cells or specialized cellular structuresCellular locomotion is an essential part of life for many organismsEarly development - neurons migrating from their point of origin to their developmental destinationLater Development - Once the neurons have found their home within the cerebral cortex they send out axons that stretch into other parts of the brainChemoattractantChemorepellentWednesday, February 24, 2010Lecaudey, et al., 2008Cellular locomotion is an essential part of life for many organismsEmbryonic development in animalsCollective movement of groups of cellsHow are cohorts of cells able to stay together as they migrate through tissue (also made of cells) and how do they know when (or if) they’re to come apart?Zebrafish cellsWednesday, February 24, 2010Cellular locomotion is an essential part of life for many organismsWound healing and tissue remodelingCells sense the loss of epithelial integrity (neighbors) which triggers cell motility and gene transcription Wednesday, February 24, 2010Cellular locomotion is an essential part of life for many organismsImmune cells - Macrophages and NeutrophilsMigrate toward chemical signals from bacteria and other pathogensWednesday, February 24, 2010Cellular locomotion is an essential part of life for many organismsImmune cells - Macrophages and NeutrophilsMigrate toward chemical signals from injured, inflamed, and dead tissue (called Necrotaxis)Wednesday, February 24, 2010Cellular locomotion is an essential part of life for many organismsPollen Tube GrowthRequired to transport non-motile sperm to ovule tissueWednesday, February 24, 2010Misregulation of cell migration contributes to disease• Congenital birth defects• Chronic inflammatory diseases (asthma & arthritis)• Cancer (metastasis)• Atherosclerosis & heart diseaseWednesday, February 24, 2010Rolling leukocytes are recruited to sites of injury or inflammationWednesday, February 24, 2010AtherosclerosisWednesday, February 24, 2010How do cell’s move?Wednesday, February 24, 2010Cellular migration is a cycle of 4 processes1. Polarization of the cell (defining front vs. back)2. Protrusion of the leading edge3. Formation of adhesive contacts with the surface4. De-adhesion and retraction of the trailing edgeWednesday, February 24, 2010Cell polarity is regulated by signaling molecules that create a “leading edge” and “trailing edge”1. Membrane receptors (GPCRs, RTKs) detect an asymmetric signal from outside the cell2. Receptors activate Ras-like small G proteins (Rho-family proteins)3. Rho-family proteins induce cytoskeletal changes at the leading (Rac, Cdc42) and trailing (Rho) edges of the cellWednesday, February 24, 2010Rho family members are Ras-like proteins that regulate cell morphology and polarityWednesday, February 24, 2010Rho protein localizes to the trailing edge of crawling neutrophilsActin / RhoWednesday, February 24, 2010Signaling during cell polarizationWednesday, February 24, 2010Cell polarization requires the orientation and capture of microtubules at the leading edgeWednesday, February 24, 20102. Protrusion• Protrusion is driven primarily by forces that are produced by actin polymerization• There are 2 types of protrusive structures in motile cells: lamellipodia (sheet-like) and filopodia (finger-like)Wednesday, February 24, 2010The structure of protrusions is dictated by actin organizationWednesday, February 24, 2010Actin dynamics in lamellipodiaWednesday, February 24, 2010Lamellipodia are composed of branched networks of short actin filamentsWednesday, February 24, 2010Actin dynamics in lamellipodia • ARP complex - nucleates growth of new filaments• Capping proteins - halt growth of filaments to keep them short• Depolymerizing proteins - break down network away from leading edgeWednesday, February 24, 2010Filopodia dynamicshttp://www.youtube.com/watch?v=VWGA7kIeE0QWednesday, February 24, 2010Filopodia are composed of long, unbranched, and bundled actin filamentsWednesday, February 24, 2010The model for filopodia formationWednesday, February 24, 20103. Formation of adhesive contacts with the substrateWednesday, February 24, 2010Cells bind to the ECM (Extra-Cellular Matrix) using transmembrane receptors called integrinsFibronectinWednesday, February 24, 2010Cell Migration Consortium http://www.cellmigration.org/index.shtml Integrins bound to ECM cluster to form “focal adhesions”Wednesday, February 24, 2010Integrins form an indirect linkage between the ECM and actin network• This link to the substrate allows the cell to exert force and gain traction in motility• The amount of tension between the cytoskeleton and the ECM is how cells “feel” the rigidity of their substrate (Durotaxis)Wednesday, February 24, 2010The ECM is secreted and maintained by fibroblastsWednesday, February 24, 2010A Cancer cell migrates in vitro through a 3-D collagen matrixLecaudey, et al., 2008Wednesday, February 24, 20104. De-adhesion and retraction of the trailing edge• Cells use actin and myosin II to pull on the trailing edge• Myosin II is activated at trailing edge by Rho• When force of
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