ANRV288-CB22-10 ARI 6 June 2006 7:31REVIEWSINADVANCEIn Vivo Migration: A GermCell PerspectivePrabhat S. Kunwar, Daria E. Siekhaus,and Ruth Lehmann∗Howard Hughes Medical Institute, Developmental Genetics Program, SkirballInstitute, Department of Cell Biology, New York University School of Medicine,New York, New York 10016-6402; email: [email protected],[email protected], [email protected]. Rev. Cell Dev. Biol.2006. 22:237–65The Annual Review ofCell and Developmental Biologyis online athttp://cellbio.annualreviews.orgdoi: 10.1146/annurev.cellbio.22.010305.103337Copyrightc 2006 byAnnual Reviews. All rightsreserved1081-0706/06/1110-0237$20.00∗Corresponding author.Key Wordschemokine, metastasis, leukocytes, G protein–coupled receptor(GPCR), phospholipids, repulsionAbstractThe basic concepts of the molecular machinery that mediates cellmigration have been gleaned from cell culture systems. However,the three-dimensional environment within an organism presents mi-grating cells with a much greater challenge. They must move be-tween and among other cells while interpreting multiple attractiveand repulsive cues to choose their proper path. They must coordi-nate their cell adhesion with their surroundings and know when tostart and stop moving. New insights into the control of these re-maining mysteries have emerged from genetic dissection and liveimaging of germ cell migration in Drosophila, zebrafish, and mouseembryos. In this review, we first describe germ cell migration in cel-lular and mechanistic detail in these different model systems. Wethen compare these systems to highlight the emerging principles.Finally, we contrast the migration of germ cells with that of immuneand cancer cells to outline the conserved and different mechanisms.237First published online as a Review in Advance on June 14, 2006Annu. Rev. Cell Dev. Biol. 2006.22. Downloaded from arjournals.annualreviews.orgby University of California - San Diego on 09/16/06. For personal use only.ANRV288-CB22-10 ARI 6 June 2006 7:31ContentsINTRODUCTION................. 238DROSOPHILA ...................... 240Summary of Normal Migration . . . 240Start: Activation of a DormantMigratory Program............ 242Repellant and Attractive Cues Linethe Migratory Path ............ 247ZEBRAFISH ....................... 249Summary of Normal Migration . . . 249Start: Activation of the MigratoryProgram RequiresTranscription and dead end ..... 250SDF1/CXCR4: the MasterRegulators of Migration ....... 250MOUSE ............................ 251Summary of Normal Migration . . . 251Start by Repulsion ................ 251Multiple Cues Line theMigratory Path................ 252EMERGING CONCEPTS ......... 253Intrinsic (Cell-Autonomous) andExtrinsic(Cell-Nonautonomous) FactorsControl the Initiation ofMigration ..................... 253G Protein–Coupled ReceptorActivation in Germ CellsMediates Directionality . . . ..... 253A Balance of Attractive andRepellant Cues May ProvideEfficacy and Consistency to theMigratory Route .............. 253Extrinsic Signals Control theTermination of Migration ...... 254Successful Germ Cell Migration IsLinked to Survival ............. 254COMPARISON WITH OTHERMIGRATORY CELLS ........... 255An Amoeboid Migratory BehaviorAcross Evolution .............. 255Signaling Pathways thatGuide Migration .............. 255Specialized Movement:Transepithelial Migration . . . . . . 257Similarities with MetastaticCancer Cells .................. 257FUTURE QUESTIONS............ 258Chemotaxis:cellular movementtoward the highestpoint of a gradient ofan external chemicalsignalINTRODUCTIONCell migration is essential for normal devel-opment and immune defense and contributescritically to different pathological conditions(Franz et al. 2002, Horwitz & Webb 2003,Ridley et al. 2003, Vicente-Manzanares et al.2005). During normal development, the co-ordinated movement of cells during gastrula-tion creates the three-dimensional body struc-ture. During neurulation, neural crest cellsmigrate away from their site of origin andfollow complicated migratory routes to giverise to many different tissues, such as thebranchial arches, glia, and melanocytes. Im-mune cells migrate toward infected sites toprotect the body. In cancer, cells move awayfrom their origin and colonize different tissuesin a directed fashion (Friedl & Wolf 2003a,Sahai 2005). The mechanics of cell migra-tion have been largely addressed in tissue cul-ture systems in which culturing conditions canbe controlled and a large number of simi-lar cells can be analyzed and readily observedusing sophisticated live-imaging techniques(Chung et al. 2001, Iijima et al. 2002, Ridleyet al. 2003, Van Haastert & Devreotes 2004).These studies have provided a framework fora mechanistic dissection of the directed cellmigration process, chemotaxis.In culture, cells are usually grown on atwo-dimensional surface, and directional mi-gration is triggered by the use of point sourcesof chemoattractants. In this environment, mi-gratory cells have an intrinsic polarity, with aflat leading edge and a pointed lagging end. Inresponse to a chemoattractant gradient, cells238 Kunwar·Siekhaus·LehmannAnnu. Rev. Cell Dev. Biol. 2006.22. Downloaded from arjournals.annualreviews.orgby University of California - San Diego on 09/16/06. For personal use only.ANRV288-CB22-10 ARI 6 June 2006 7:31persistently migrate in one direction towardthe gradient’s high point by cycling betweenphases of protrusion and adhesion at the an-terior leading edge and retraction at the rear(Pollard & Borisy 2003). When the gradientis altered to a new direction, the polarizedcell turns toward the new direction withoutnecessarily changing polarity. The intrinsicpolarity is generated by the small GTPasesCDC42 and Rac, together with PAR proteinsand other regulators of cell polarity. Direc-tional polarity is triggered by activation of Gprotein–coupled receptors (GPCRs) or tyro-sine receptor kinases in response to chemoat-tractants (Ridley et al. 2003). The interac-tion of the signal and its receptor leads tothe activation of effector molecules and ul-timately to changes in the cytoskeletal ma-chineries and adhesive properties of the cells.Because cells can measure even a shallowgradient of chemoattractant, positive feed-back loops have been proposed as a means toamplify small differences in receptor activa-tion between the front and back of the cell.In migrating Dictyostelium and neutrophils,for example, this