FGF secretion represents a comprehensive example of the ways that HSPGs can influence paracrine factor diffusion. Cells secrete FGFs into the extracellular matrix, where the FGFs can interact with a diversity of HSPGs that function to both modulate the diffusion of FGF and influence FGF-FGFR binding (Balasubramanian and Zhang 2015). Like all proteoglycans, HSPGs possess side chains of sugar molecules—glycosaminoglycans—that vary in length and type, and different forms of HSPG-FGF interactions can differently shape the FGF gradient. Specifically, the morphogen gradient of Fgf8 is thought to be established through a source-sink model (also known as a “secretion-diffusion-clearance” mechanism; Yu et al. 2009). In this model, cells secreting Fgf8 are the source of the morphogen, and the receiving cells provide the sink through mechanisms of binding, internalization, or protein degradation for clearance of Fgf8 (Balasubramanian and Zhang 2015). Michael Brand’s lab tested this model in the zebrafish gastrula by microinjecting a cluster of cells with mRNA encoding Fgf8 fused to GFP. When these cells translated this mRNA, they produced and secreted Fgf8 complexed with green fluorescent protein. This allowed the researchers to quantify the amount of Fgf8 in the extracellular space at varying distances from the microinjected cells using fluorescence correlation spectroscopy (Figure 1A, B). Remarkably, the researchers were able to visualize an Fgf8-GFP gradient that differed under different circumstances (Figure 1C): free diffusion of the ligand achieved the greatest distance traveled; “directed diffusion” along HSPG fibers fostered rapid movement over several cell distances; “confined clustering” of Fgf8 on dense HSPG matrices significantly restricted diffusion; and endocytosis internalized the Fgf8-FGFR complex for lysosomal degradation in receiving cells (Yu et al. 2009; Bökel and Brand 2013). Thus, the target tissue is not passive. It can promote diffusion, retard diffusion, or degrade the paracrine factor.
Balasubramanian, R. and X. Zhang. 2016. Mechanisms of FGF gradient formation during embryogenesis. Semin. Cell Dev. Biol. 53: 94–100.
Bökel, C. and M. Brand. 2013. Generation and interpretation of FGF morphogen gradients in vertebrates. Curr. Opin. Genet. Dev. 23: 415–422.
Yu, S. R., M. Burkhardt, M. Nowak, J. Ries, Z. Petrásek, S. Scholpp, P. Schwille and M. Brand. 2009. Fgf8 morphogen gradient forms by a source-sink mechanism with freely diffusing molecules. Nature 461: 533–536.
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