Pharyngula

Pair-rule genes

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The general pattern of developing positional information in Drosophila starts out relatively simply and gets increasingly complicated as time goes by. Initially, there is a very broad distribution of a gradient of a maternal morphogen. That morphogen then triggers the expression of narrower (but still fairly broad) bands of aperiodic gap genes. The next step in this process is to turn on sets of genes in narrow, periodic bands that correspond to body segments. This next set of genes are called the pair-rule genes, because they do something surprising and rather neat: they are turned on in precisely alternating bands. In the picture above, for instance, one pair-rule gene, even-skipped, has been stained blue, and it is expressed in parasegment* 1, 3, 5, 7, etc. Another, fushi tarazu, has been stained brown, and this gene is turned on in parasegments 2, 4, 6, 8, etc.

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Compared to the gap genes, the pair-rule genes are a nightmare of complexity and special rules. The gap genes have elaborate interactions among themselves to set up their domains of expression, and the gap genes in turn activate and repress the primary pair-rule genes (even-skipped, hairy, and runt), and they in turn interact with each other and with a set of secondary pair-rule genes (fushi tarazu, odd-skipped, paired, sloppy-paired). Some overlap in expression and activate each other, others have complementary regions of expression and inhibit each other. As the grossly simplified diagram to the left shows, even-skipped (eve), for instance, up-regulates hairy (h), but wherever eve is turned on, it turns off runt and fushi tarazu (ftz).

Oh, that biology were actually so simple.

I’ve been reading a paper on the regulatory logic of the pair-rule genes by Sanchez and Thieffry (2003); it’s an interesting combination of thorough review of pair-rule interactions, and an attempt to model those interactions as logical formalisms. The model is derived from observations of the pattern of gene expression and epigenetic experiments that track regulatory interactions by knocking out genes or overexpressing them.

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Here, for example is a summary of the segmental pattern of these genes in the early embryo (top half) and late embryo (bottom half). You can see that we go from a very broad, fuzzy pattern for each to a much tighter, harder-edged band. (OK, it’s a cartoon, so you can’t really see it there—so look at the photo to the right of eve and ftz in the late embryo. Sharp! Cells express it or they don’t, and they lie in discrete lines.)


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Schematic representation of the main pair-rule gene expression domains. The initial expression patterns of pair-rule genes form seven bell-shaped domains (top), which are later refined into final narrow stripes (bottom). Gene hairy is shown on the top of the figure because this gene ceases its expression earlier than its target genes ftz and run, before the final refinement process leading to the narrow stripes of the pair-rule genes directly involved in en and wg activation. Five different regions (I?V) defining two parasegment borders are indicated. The interactions between the pair-rule genes are the same in all locations along the anterior?posterior axis where the parasegment boundaries, represented by thick lines. These are flanked by two regions expressing wg (region I or IV) and en (region II or V) respectively. Regions IIIa and IIIb correspond to the middle of the parasegment, each representing a region adjacent to the en or wg expressing cells within the parasegment. As a whole, region III is characterized by the lack of expression of both en and wg and by the expression of odd. The primary and secondary pair-rule genes are shown in graded shadow and empty boxes, respectively. Genes symbols: runt (Run), even-skipped (Eve), fushi-tarazu (Ftz), odd-skipped (Odd), paired (Prd), sloppy-paired (Slp), engrailed (En) and wingless (Wg).

Very nifty, huh? We’re not done yet, though. The authors have put together a diagram to show all the logical interactions, negative and positive, in this system:

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Final pair-rule expression domains after the refinement process and interactions between these genes. Solid arrows stand for positive interactions, dotted blunt arrows indicate negative interactions.

Now that’s the kind of mess you get with a few million years of evolutionary tweaking. The idea is that there is a “pair-rule module”, a simpler underlying scheme that inhibits complementary genes to generate discrete, exclusive domains of expression. What evolution does, though, is spawn duplicate copies that then are free to acquire a slightly different regulatory logic…and what you end up with is an elaborate assortment of partially redundant, overlapping units, each with minor variations. Drosophila has gone a long way down the road towards hard-coding specialized functions into the regulation of these genes, and the general module is hard to pick out anymore.

One reason developmental biologists have become increasingly interested in looking at these genes in other organisms is the idea that common features between flies, beetles, grasshoppers, fish, mice, etc. will help us more clearly see what are the core modules and what are the late-evolving rococo additions.

Oh, and yes, we are finding these genes in other organisms. I’ve mentioned hairy homologs before as key regulators of segmental organization in vertebrates.


*One somewhat confusing issue I won’t get into now is the segment/parasegment distinction. Morphological segments are the distinctly bounded regions you can see in the insect’s body; think of the bands of cuticle you can see in the adult fly’s abdomen, for instance. Development is always throwing odd discoveries at you, though. It turns out that the fundamental genetic/molecular unit is actually half a segment out of phase with the morphology, hence it is called a parasegment.


Sanchez L, Thieffry D (2003) Segmenting the fly embryo: a logical analysis of the pair-rule cross-regulatory module. J Theor Biol 224(4):517-537.