Heparan Sulfate Proteoglycans Regulate Fgf Signaling and Cell Polarity during Collective Cell Migration

• HSPGs are crucial components of the Wnt/β-catenin/Fgf signaling feedback loop
• Fgf signal transduction is HSPG dependent in the primordium
• HSPGs limit Fgf ligand diffusion away from the primordium
• HSPGs regulate the cell polarity of collectively migrating placodal cells

SummaryCollective cell migration is a highly regulated morphogenetic movement during embryonic development and cancer invasion that involves the precise orchestration and integration of cell-autonomous mechanisms and environmental signals. Coordinated lateral line primordium migration is controlled by the regulation of chemokine receptors via compartmentalized Wnt/β-catenin and fibroblast growth factor (Fgf) signaling. Analysis of mutations in two exostosin glycosyltransferase genes (extl3 and ext2) revealed that loss of heparan sulfate (HS) chains results in a failure of collective cell migration due to enhanced Fgf ligand diffusion and loss of Fgf signal transduction. Consequently, Wnt/β-catenin signaling is activated ectopically, resulting in the subsequent loss of the chemokine receptor cxcr7b. Disruption of HS proteoglycan (HSPG) function induces extensive, random filopodia formation, demonstrating that HSPGs are involved in maintaining cell polarity in collectively migrating cells. The HSPGs themselves are regulated by the Wnt/β-catenin and Fgf pathways and thus are integral components of the regulatory network that coordinates collective cell migration with organ specification and morphogenesis.

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