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Boundary Creation by Extracellular Signals

As the syncytial fly embryo becomes cellular and undergoes gastrulation, the movement of proteins and mRNAs through the common cytoplasm of a syncytium is over. Further cell-fate specification is controlled primarily by cells communicating with one another through secreted extracellular signals. In this section, we examine how three signaling path ways, activated by Hedgehog (Hh), Wingless (Wg, a member of the Wnt family), and TGFp, create boundaries between cell types during Drosophila development. The Wingless and Hedgehog proteins are encoded by segment-polarity genes, so named because they affect the orientation of surface features of the cuticle, such as bristles. The events discussed here are representative of what happens in virtually all tissues and all animals to specify cell types and create boundaries between different types.

Two Secreted Signals, Wingless and Hedgehog, Create Additional Boundaries Within Segments of Cellular Fly Embryos

As we saw in Section 15.4, the 14 segment primordia in the early Drosophila embryo are defined by various pair-rule proteins, with each protein located in seven stripes that alternate with stripes of cells that do not make the protein. The segment-polarity gene engrailed, which encodes a transcription factor, is expressed in the most anterior cell in each pri-mordium, forming 14 Engrailed stripes. Transcription of engrailed is activated and repressed by various pair-rule proteins. In each eight-cell repeat unit established by the pair-rule proteins, engrailed is transcribed in cells 1 and 5. Recall that the pair-rule proteins produced in cells 1 through 4 differ from those produced in cells 5 through 8 (see Figure 15-24b). Although the transcriptional regulation of engrailed is the same in cell 1 in all the eight-cell repeats, it cannot be the same in cells 1 and 5 of a repeat. Thus two different combinations of pair-rule proteins must activate transcription of engrailed; so a seemingly simple repeating pattern masks a striking difference in regulation.

Another segment-polarity gene called wingless becomes active at about the same time as engrailed. It also is expressed in single-cell-wide stripes, adjacent to the Engrailed stripes and just one cell farther anterior (see Figure 15-24b). Wingless is a secreted signaling protein, a member of the Wnt protein family found in most or all animals. With the production of Wingless, the cells of the fly embryo stop ignoring one another and begin communicating through signals. In adjacent Engrailed-producing cells, the Wingless signal maintains the expression of another segment-polarity gene called hedgehog (hh), which also encodes an external signal. Expression of hedgehog is initially activated by Engrailed, a transcription factor that has both activating and repressing abilities. Engrailed activates hedgehog directly and represses a gene encoding a repressor of hedgehog, thereby indirectly promoting hedgehog expression. In the fly embryo, the Wingless and Hedgehog signals, produced in adjacent stripes of cells, form a positive feedback loop, with each maintaining expression of the other across the boundary (Figure 15-29).

The Wingless and Hedgehog signals control which cell types form in which positions, creating additional boundaries beyond those established by pair-rule proteins. Even

Primordium of future body segment

Anterior

Anterior

Posterior

Posterior v

Parasegment v

Parasegment

▲ FIGURE 15-29 Role of Hedgehog (Hh) and Wingless (Wg) in boundary creation between parasegments in Drosophila embryo. Hedgehog is necessary to maintain wingless transcription, and, conversely, Wingless is required to maintain hedgehog. These two secreted signals play a key role in patterning the epidermis. Both signaling proteins act on cells in addition to those indicated by the arrows.They act through the signal-transduction pathways shown in Figures 15-31 and 15-32. [See M. Hammerschmidt et al., 1997, Trends Genet. 13:14.]

before Wingless- or Hedgehog-induced morphological features are evident, the prospective cell fates can be detected by the production of specific transcription factors. Both Hedgehog and Wingless can act as morphogens, with different concentrations inducing different fates in receiving cells (see Figure 15-11b). Cells that receive a large amount of Wingless turn on certain genes and form certain structures; cells that receive a smaller amount turn on different genes and thus form different structures. The same idea applies to the effects of different amounts of Hedgehog on receiving cells. As Wingless and Hedgehog are secreted from their source cells, they theoretically could move and signal in both directions. Recent work, however, shows that a signal can act mostly in one direction, anterior in the case of Wingless. This directional preference results from active destruction of much of the Wingless protein that moves posteriorly.

Having seen when the Drosophila Hedgehog and Wnt-type signals first begin to act in fly development, we take a closer look at the operation of these pathways. Both pathways participate in the development of many different tissues in Drosophila and most other animals.

this process includes adding cholesterol to a glycine residue, splitting the molecule into two fragments, and leaving the N-terminal signaling fragment with an attached hydrophobic cholesterol moiety. The C-terminal domain of the precursor, which catalyzes this reaction, is found in other proteins and may promote the linkage of these proteins to membranes by the same autoproteolytic mechanism. A second modification to Hedgehog, the addition of a palmitoyl group to the N-terminus, makes the protein even more hydrophobic. Together, the two modifications may tether Hedgehog to cells, thereby affecting its range of action in tissue. Spatial restriction plays a crucial role in constraining the effects of powerful inductive signals.

83 Hh precursor

45 kDa

83 Hh precursor

45 kDa

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