Soaking up signal: Endocytosis controls spreading and effective signaling range of Fgf8 protein

October 25, 2004

In a new paper, researchers have reported evidence that cells can actively regulate the levels of secreted signaling proteins that they encounter in the context of their extracellular environment. The finding is important because cells in developing tissues are extremely sensitive to such protein signals, and thus the range of these signals within a given tissue must be precisely regulated to prevent morphological defects from arising during development.

Fibroblast Growth Factors are a group of signaling molecules that influence a wide range of cellular decisions, such as induction of response genes, cell proliferation, and cell differentiation. One member of this growth factor group, Fgf8, has key functions during the development of such structures as the vertebrate brain, heart, and inner ear. Growth factors such as Fgf8 are emitted by particular cells and travel within tissues in the extracellular space, where they signal to the "target" cells they encounter. Spatial control of this signaling is crucial during development, but the mechanisms by which the spreading of Fgf8 protein is controlled in a field of target cells are unknown.

In seeking to better understand how this signaling is controlled, researchers Steffen Scholpp and Michael Brand of the University of Technology, Dresden and the Max Planck Institute-CBG, Dresden, have investigated the role of Fgf8 in the development of nascent neuroectoderm tissue in living zebrafish embryos. Their observation of molecularly tagged Fgf8 protein by confocal microscopy serves as one of the first examples of direct visualization of the spread of signaling molecules in an intact animal.

The researchers found that spreading of Fgf8 through target tissue is controlled by endocytosis--i.e., internalization of Fgf8 protein by the cell--and subsequent degradation of Fgf8 within the cell's lysosome. This process, termed 'restrictive clearance,' saps Fgf8 from extracellular spaces and limits the spread of the signal. If internalization is inhibited, Fgf8 protein accumulates extracellularly, spreads further, and activates target gene expression over a greater distance. Conversely, enhanced internalization increases Fgf8 uptake and shortens its effective signaling range. These new results suggest that growth factors are able to spread extracellularly by a diffusion-based mechanism. An especially important implication of the work is that target cells can actively influence the availability of signals to other target cells through uptake and subsequent degradation of growth factors and other signaling proteins.
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Steffen Scholpp and Michael Brand: "Endocytosis Controls Spreading and Effective Signaling Range of Fgf8 Protein"

Publishing in Current Biology, Vol. 14, Issue 20, October 26, 2004, pages 1834-1841.

Cell Press

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