Asymmetric Movement of Wingless Protein in the Epidermis of Drosophila

New discoveries create new questions, and often these new questions challenge the assumptions that were thought to be well established. One of these assumptions is that morphogens (such as Wingless and Hedgehog proteins) act by diffusing through the space around the cells. This would create the gradient highest at the source, tapering down as the distance from the source increases. However, in such instances, one would expect to find diffusion to be radial from the source. The Wingless protein should diffuse to the cells in front of it at the same rate as it does to the cells behind it.

But this is not the case. While the initial stages of Wingless movement (at embryonic stage 9) appear to be symmetric around its expression domain, slightly later (at stage 11), there is a marked asymmetry. Wingless protein spreads as a gradient anteriorly, but it does not appear to spread much at all posteriorly (van den Heuvel et al., 1989; Gonzales et al., 1991). This asymmetric protein distribution is reflected in the asymetric action of the Wingless protein. It can effect its direct neighbors posteriorly, but it can cause naked cuticle for 4 cell diameters anteriorly.

There have been several hypotheses put forth to explain this. The first hypothesis (Kerszberg and Wolpert, 1998; Figure 1A) is that diffusion is not in the soluble extracellular fluid. Rather, it is mediated by receptors on the cell surface. The Wingless protein might be shuttled from one cell to another on the surfaces of cells. If the receptors were asymmetrically positioned on the cells, the net transport would be in one direction. Since Wingless binds to glycosaminoglycans, these molecules might also cause a net transport in one direction.

Figure 1
Figure 1  

The second type of hypothesis involves Wingless going from cell to cell via membrane-bound vesicles. That is, instead of diffusing, the protein would be passed directionally from one side of the cell to another (Gonzales et al, 1991; Figure 1B). In mutations of Shibire, where endocytosis is blocked, Wingless does not act at a distance (Bejsovec and Wieschaus, 1995).

A third model has recently been proposed by Pfeiffer and colleagues (2000). In embryos of the fruit fly Drosophila, the wingless (wg) gene is transcribed in narrow stripes of cells abutting the source of Hedgehog protein. They found that these cells or their progeny are free to roam towards the anterior (Figure 1C). As they do so, they no longer receive the Hedgehog signal, and they stop transcribing the wingless gene. However, although they are no longer transcribing wingless, the cells leaving the expression domain have retained Wingless protein in their secretory vesicles and carry it forwards over a distance of up to four cell diameters. Experiments using a membrane-tethered form of Wg (which cannot diffuse) showed that this mechanism is sufficient to account for the normal range of Wg.

Wingless protein may be able to travel in several ways, but diffusion through a soluble medium seems to have been ruled out.

Literature Cited

Bejsovec, A. and Wieschaus, E. 1995. Signaling activities of the Drosophila wingless gene are separately mutable and appear to be transduced at the cell surface. Genetics 139: 309-320.

Gonzalez, F., Swales, L., Bejsovec, A., Skaer, H., and Martinez Arias, A. 1991. Secretion and movement of wingless protein in the epidermis of the Drosophila embryo. Mech Dev 35: 43-54.

Kerszberg, M. and Wolpert, L. 1998. Mechanisms for positional signalling by morphogen transport: a theoretical study. J Theor. Biol. 191: 103-114.

Pfeiffer, S., Alexandre, C., Calleja, M., and Vincent JP. 2000. The progeny of wingless-expressing cells deliver the signal at a distance in Drosophila embryos. Current Biol. 10: 321-324.

van den Heuvel, M., Nusse, R., Johnston, P., and Lawrence, P. A. 1989. Distribution of the wingless gene product in Drosophila embryos: a protein involved in cell-cell communication. Cell 59: 739-749.

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