XB-ART-55266Front Cell Dev Biol January 1, 2018; 6 83.
Using Zebrafish to Study Collective Cell Migration in Development and Disease.
Cellular migration is necessary for proper embryonic development as well as maintenance of adult health. Cells can migrate individually or in groups in a process known as collective cell migration. Collectively migrating cohorts maintain cell-cell contacts, group polarization, and exhibit coordinated behavior. This mode of migration is important during numerous developmental processes including tracheal branching, blood vessel sprouting, neural crest cell migration and others. In the adult, collective cell migration is important for proper wound healing and is often misappropriated during cancer cell invasion. A variety of genetic model systems are used to examine and define the cellular and molecular mechanisms behind collective cell migration including border cell migration and tracheal branching in Drosophila melanogaster, neural crest cell migration in chick and Xenopus embryos, and posterior lateral line primordium (pLLP) migration in zebrafish. The pLLP is a group of about 100 cells that begins migrating around 22 hours post-fertilization along the lateral aspect of the trunk of the developing embryo. During migration, clusters of cells are deposited from the trailing end of the pLLP; these ultimately differentiate into mechanosensory organs of the lateral line system. As zebrafish embryos are transparent during early development and the pLLP migrates close to the surface of the skin, this system can be easily visualized and manipulated in vivo. These advantages together with the amenity to advance genetic methods make the zebrafish pLLP one of the premier model systems for studying collective cell migration. This review will describe the cellular behaviors and signaling mechanisms of the pLLP and compare the pLLP to collective cell migration in other popular model systems. In addition, we will examine how this type of migration is hijacked by collectively invading cancer cells.
PubMed ID: 30175096
PMC ID: PMC6107837
Article link: Front Cell Dev Biol
Species referenced: Xenopus
Genes referenced: cdh11 ctnnb1 cxcl12 cxcr4 dkk1 dkk2 dll1 egfr ereg jag1 lef1 mapk1 notch1 notch3 pllp tcf3 tfcp2 tnc
Article Images: [+] show captions
|Figure 1. Different modes of collective cell migration. (A) Chain migration of neural crest cells. Cells start as a cohesive cluster at the neural plate border and then delaminate away and migrate as chains toward the Cxcl12a source. Cells display transient adherens junctions. (B) Cluster cell migration of border cells in Drosophila melanogaster. Cells maintain tight adherens junctions while migrating with the leading cell in front exhibiting extensive protrusive behavior. These cells migrate toward the EGF/PVF-1 source. (C) Branching morphogenesis of Drosophila melanogaster trachea. While the leading cell migrates toward the source of Fgf, trailing cells form tube like structures. (D) Epithelial sheet migration-wound healing. Leading cells on either side of the wound migrate toward each other to close the wound. Leading cells extend filopodial protrusions toward each other. Follower cells extend cryptic lamellipodia underneath cells in front of them. Adherens junctions are maintained during migration.|
|Figure 2. Posterior Lateral Line formation (pLL) and posterior Lateral Line Primordium (pLLP) migration. (A) pLLP begins migrating around 20 hours post-fertilization (hpf). (B) At 30 hpf the pLLP has migrated about half way down the trunk and deposited 3 neuromasts (NMs). (C) pLLP migration is complete at 48 hpf with the deposition of the terminal cluster of NMs.|
|Figure 3. Schematic of the posterior Lateral Line Primordium (pLLP). In blue are the 2–3 leader cells. In green is the leading region. In orange is the trailing region. In white is a depositing neuromast. The top schematic is a lateral view of pLLP cells. The bottom schematic is a dorsal/ventral view. Arrows point to proto-neuromasts/rosettes.|
|Figure 4. Signaling and chemotactic pathways active during pLLP migration. (A) Signaling pathways active during pLLP migration. Wnt signaling is active in the leading region (blue and green cells). Wnt signaling initiates expression of Fgf3/10a in the leading cells. Fgf 3/10a activate Fgf signaling in the trailing region (orange). Wnt signaling initiates expression of sef , an inhibitor of Fgf signaling. Fgf signaling initiates expression of dkk1 and dkk2, inhibitors of Wnt signaling. Thus the two signaling regions are maintained through mutual inhibition. (B) Chemokine signaling during pLLP migration. Green strip indicates the internal Cxlc12a generated within the pLLP. cxcr4b chemokine receptor (yellow) is expressed in the leading 2/3 of the pLLP. cxcr7b is expressed in the trailing 1/3 of the pLLP (purple).|
|Figure 5. Signaling pathways for rosette formation and proto-NM maturation. (A) Hypothesized signaling that initiates apical constriction. Fgf signaling activates Ras and MAPK. This initiates transcription of schroom3. Schroom3 interacts with Rock 2a (Rho Kinase) and activates non-muscle myosin at the membrane, which initiates apical constriction of cells through reorganization of the actin cytoskeleton. (B) proto-NM maturation signaling. Fgf luminal signaling initiates atoh1a and notch3 expression. Atoh1a induces expression of deltaA and fgf10a. DeltaA interaction with Notch3 initiates lateral inhibition allowing for atoh1a expression to be localized to the central cell (hair cell precursor) and surrounding cells to remain as supporting cells.|
|Figure 6. A potential model of collective cell invasion. Small groups of cells high in canonical Wnt signaling break off from the primary tumor, invade surrounding tissue, and enter the blood stream. This cluster then extravisates from the blood stream homing onto to a chemokine source, such as CXCL12. The mechanisms of blood vessel intravisation and extravasation by cell clusters are not known (question marks). It has been speculated that behaviors of such clusters exhibit many similarities to leading front cells present in collective cell migration during embryogenesis. Adherens junctions are maintained throughout invasion process.|
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