Slide 1Slide 2Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19Slide 20Slide 21Slide 22Slide 23Slide 24Slide 25Slide 26Slide 27Slide 28Slide 29Slide 30Slide 31Slide 32Slide 33Slide 34Slide 35Slide 36Slide 37Slide 38Slide 39Slide 4002.24.10Lecture 17 - Cell motilityThe 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...“-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 substrate“-Taxis”, a form of cell signaling1. Reception of signal2. Transduction of signal3. Cellular responseCell motility towards or away from the signalCellular locomotion is an essential part of life for many organismsSingle celled protozoa - Dictyostelium discoideumhttp://www.youtube.com/watch?v=VWGA7kIeE0QCellular locomotion is an essential part of life for many organismsSingle celled protozoa - Dictyostelium discoideumhttp://www.youtube.com/watch?v=VWGA7kIeE0QMahadeo and Parent, 2006QuickTime™ and aPhoto decompressorare needed to see this picture.Embryonic development in animalsMovements of autonomous cells or specialized cellular structuresQuickTime™ and aPhoto decompressorare needed to see this picture.Cellular 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 brainChemoattractantChemorepellentQuickTime™ and aH.264 decompressorare needed to see this picture.8Lecaudey, 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 cellsCellular 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 QuickTime™ and aMPEG-4 Video decompressorare needed to see this picture.QuickTime™ and ampeg4 decompressorare needed to see this picture.Cellular locomotion is an essential part of life for many organismsImmune cells - Macrophages and NeutrophilsMigrate toward chemical signals from bacteria and other pathogensCellular 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)Cellular locomotion is an essential part of life for many organismsPollen Tube GrowthRequired to transport non-motile sperm to ovule tissueQuickTime™ and aVideo decompressorare needed to see this picture.Misregulation of cell migration contributes to disease•Congenital birth defects•Chronic inflammatory diseases (asthma & arthritis)•Cancer (metastasis)•Atherosclerosis & heart diseaseRolling leukocytes are recruited to sites of injury or inflammationQuickTime™ and aMPEG-4 Video decompressorare needed to see this picture.AtherosclerosisHow do cell’s move?Cellular 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 edgeQuickTime™ and aYUV420 codec decompressorare needed to see this picture.Cell 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 cellRho family members are Ras-like proteins that regulate cell morphology and polarityRho protein localizes to the trailing edge of crawling neutrophilsActin / RhoSignaling during cell polarizationCell polarization requires the orientation and capture of microtubules at the leading edge2. 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)The structure of protrusions is dictated by actin organizationActin dynamics in lamellipodiaQuickTime™ and aTIFF decompressorare needed to see this picture.Lamellipodia are composed of branched networks of short actin filamentsActin 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 edgeFilopodia dynamicsQuickTime™ and a decompressorare needed to see this picture.http://www.youtube.com/watch?v=VWGA7kIeE0QFilopodia are composed of long, unbranched, and bundled actin filamentsThe model for filopodia formation3. Formation of adhesive contacts with the substrateCells bind to the ECM (Extra-Cellular Matrix) using transmembrane receptors called integrinsFibronectinQuickTime™ and aPhoto decompressorare needed to see this picture.Cell Migration Consortium http://www.cellmigration.org/index.shtml Integrins bound to ECM cluster to form “focal adhesions”Integrins 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)The ECM is secreted and maintained by fibroblastsQuickTime™ and aVideo decompressorare needed to see this picture.A Cancer cell migrates in vitro through a 3-D collagen matrixLecaudey, et al., 20084. De-adhesion and retraction of the trailing edge•Cells use actin and
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