Editors' ChoiceDevelopment

Remember That Gradient?

Science's STKE  29 Nov 2005:
Vol. 2005, Issue 312, pp. tw420
DOI: 10.1126/stke.3122005tw420

During early development, morphogen gradients provide information that instructs the differentiation of distinct cell types in proper spatial order. Exposure of cells to a specific concentration of morphogen can specify cell fate, but the exposure to morphogen does not need to be continuous for the several hours needed to complete execution of the gene expression program that drives the cell's response. Jullien and Gurdon explored how cells "remember" a brief exposure to morphogen by studying responses of Xenopus embryo cells to activin. Exposure of cells to activin for 10 minutes resulted in changes in gene expression several hours later. This response appeared to require continuous receptor signaling because it could be inhibited at later stages by a pharmacological inhibitor of kinase activity of the activin receptor. Continued signaling also appeared to require receptor internalization, because a dominant-negative form of dynamin that prevents internalization of receptors from the plasma membrane inhibited activin-dependent gene expression when injected into embryonic cells. Expression of mutant Rab proteins (a small guanosine triphosphatase) that increase trafficking of membrane protein through the lysosomal pathway (and thus increase the rate at which they are degraded) did not affect the "memory" of the activin signal. Thus, the authors conclude that the signaling receptors have not yet entered the degradation pathway. Rather, it seems to be a critical persistence of vesicles moving from the plasma membrane to the lysosome that accounts for the signal. Ubiquitination of receptors is known to influence their sorting. Indeed pharmacological inhibition of the proteasome enhanced activin signaling, whereas enhancement of receptor movement to the lysosome by overexpression of a receptor ubiquitin ligase complex suppressed the transcriptional response. Thus, the authors propose that receptors activated by brief exposure to activin provide a prolonged signal as they continue to signal from endosomes that have not yet been targeted to lysosomes, where the signal is finally extinguished.

J. Jullien, J. Gurdon, Morphogen gradient interpretation by a regulated trafficking step during ligand-receptor transduction. Genes Dev. 19, 2682-2694 (2005). [Abstract] [Full Text]