The Role of Differential Gene Expression in Establishing Body Segmentation

Insects such as the fruit fly Drosophila melanogaster develop a highly modular body composed of different types of segments. Complex interactions of different sets of genes underlie the pattern formation of segmented bodies.

Unlike the body segments of segmented worms such as earthworms, which are all essentially alike, the segments of the Drosophila body are clearly different from one another. The adult fly has an anterior head (composed of several fused segments), three different thoracic segments, and eight abdominal segments at the posterior end. In the Drosophila larva, the thoracic and abdominal segments all appear to be similar, but they have already received their instructions to form these specialized adult segments. Several types of genes are expressed sequentially in the embryo to define these segments. The first step in this process is to establish the polarity of the embryo.

Leafy mutant

Maternal effect genes encode morphogens that determine polarity

Like those of the sea urchin, Drosophila eggs and larvae are characterized by unevenly distributed cytoplasmic determinants (see Figure 19.8). These molecules, which include both mRNAs and proteins, are the products of specific maternal effect genes. The maternal effect genes are transcribed in the mother's ovarian cells, which surround and nurture the developing egg and deliver the gene products to specific regions of the egg as it forms. Maternal effect genes exert their effects on the embryo regardless of the genotype of the father. Their products establish the dorsal-ventral (back-belly) and anterior-posterior (head-tail) axes of the embryo.

The fact that these morphogens specify these axes was established by the results of experiments in which cytoplasm was transferred from one egg to another. Females that are ho-mozygous for a particular mutation of the maternal effect gene bicoid produce larvae with no head and no thorax. However, if the eggs of these females are inoculated at the anterior end with cytoplasm from the anterior region of a wildtype egg, the treated eggs develop into normal larvae. Conversely, removal of 5 percent or more of the cytoplasm from the anterior end of a wild-type egg results in an abnormal larva that looks like a bicoid mutant larva.

Another maternal effect gene, nanos, plays a comparable role in the development of the posterior end of the larva. Eggs from homozygous nanos mutant females develop into larvae with missing abdominal segments. Injecting cytoplasm from the posterior region of a wild-type egg into a nanos mutant egg allows normal development. These findings show that, in wild-type larvae, the overall framework of the anterior-posterior axis is laid down by the activity of these two maternal effect genes (Figure 19.14).

After the axes of the embryo are determined, the next step in pattern formation is the determination of the larval segments.

Maternal Effect Genes

Leafy mutant









The concentration of Bicoid protein is highest at the embryo's anterior end (bright yellow in this photograph).



The concentration of Bicoid protein is highest at the embryo's anterior end (bright yellow in this photograph).

tions in segment polarity genes can result in segments in which posterior structures are replaced by reversed (mirror-image) anterior structures.

Finally, after the basic pattern of segmentation has been established by the segmentation genes, differences between the segments are mediated by the activities of homeotic genes. These genes are expressed in different combinations along the length of the body and tell each segment what to become. Homeotic genes are analogous to the organ identity genes of plants.

The maternal effect, segmentation, and homeotic genes interact to "build" a Drosophila larva step by step, beginning with the unfertilized egg.

The color of the gradient moves from orange to red as Bicoid I concentration decreases into the dark blue posterior end.

High n o C

-Bicoid protein

Nanos protein

Anterior of embryo

Posterior of embryo

19.14 Bicoid and Nanos Protein Gradients Provide Positional Information The anterior-posterior axis of Drosophila arises from morphogens produced by the maternal effect genes bicoid and nanos.The gradients of these morphogens control the developing body's polarity.

Segmentation and homeotic genes act after the maternal effect genes

The number, boundaries, and polarity of the larval segments are determined by proteins encoded by the segmentation genes. These genes are expressed when there are about 6,000 nuclei in the embryo. These nuclei all look the same, but in terms of gene expression, they are not.

The products of the maternal effect genes set the segmentation genes in motion. Three classes of segmentation genes act, one after the other, to regulate finer and finer details of the segmentation pattern (Figure 19.15):

► Gap genes organize broad areas along the anterior-posterior axis. Mutations in gap genes result in gaps in the body plan—the omission of several larval segments.

► Pair rule genes divide the embryo into units of two segments each. Mutations in pair rule genes result in embryos missing every other segment.

► Segment polarity genes determine the boundaries and anterior-posterior organization of the segments. Muta-

Drosophila development results from a transcriptionally controlled gene cascade

One of the most striking and important observations about development in Drosophila—and in other animals—is that it results from a sequence of changes, with each change triggering the next. This sequence, or cascade, is largely controlled at the levels of transcription and translation.

Most unfertilized eggs are storehouses of mRNAs, which are supplied by the mother to support protein synthesis dur-

Maternal effect genes determine the anterior posterior axis, and induce three classes of segmentation genes.

Gap genes define several broad areas and regulate.

Maternal effect genes determine the anterior posterior axis, and induce three classes of segmentation genes.

Gap genes define several broad areas and regulate.

Drosophila Maternal Gene Nanos Bicoid

.segment polarity genes that determine the boundaries and anterior-posterior orientation of each segment.

Once segments are established, homeotic genes define the role of each segment.

.segment polarity genes that determine the boundaries and anterior-posterior orientation of each segment.

Once segments are established, homeotic genes define the role of each segment.

19.15 A Gene Cascade Controls Pattern Formation in the Drosophila Embryo Gap, pair rule, and segment polarity genes are collectively referred to as the segmentation genes. The shading shows the locations of their gene products in the embryo.

ing the early stages of embryonic development. Indeed, zygotes and early embryos do not carry out transcription. Only after several cell divisions does transcription begin, forming the mRNAs needed for later development.

Cytoplasmic segregation of the prefabricated mRNAs in the egg provides positional information. Before the Drosophila egg is fertilized, mRNA for the Bicoid protein is localized at the end that is destined to become the anterior end of the fly. After the egg is fertilized and laid, nuclear divisions begin. (In Drosophila, cytokinesis does not begin right away; until the thirteenth nuclear division, the embryo is a single, multinucleated cell called a syncytium.) At this early point, bicoid mRNA is translated, forming Bicoid protein, which diffuses away from the anterior end, establishing a gradient. At the posterior end, the Nanos protein forms a gradient in the other direction. Thus each nucleus in the developing embryo is exposed to a different concentration ratio of Bicoid and Nanos proteins.

The two morphogens regulate the expression of the gap genes, although in different ways. The Bicoid protein affects their transcription, while the Nanos protein affects their translation. The high concentrations of Bicoid protein in the anterior portion of the egg turn on a gap gene called hunchback, while simultaneously turning off another gap gene, Kruppel. Nanos at the posterior end reduces the translation of hunchback, so a difference in the concentration of these two gap genes' products at the two ends is established.

The proteins encoded by the gap genes control the expression of the pair rule genes. Many pair rule genes, in turn, encode transcription factors that control the expression of the segment polarity genes, giving rise to a complex, striped pattern (see Figure 19.15) of expression that foreshadows the segmented body plan of Drosophila.

By this point, each nucleus of the embryo has been exposed to a distinct set of transcription factors. The segmented body pattern of the larva has been established even before any sign of segmentation is visible. When the segments do appear, they are not all identical, because the homeotic genes specify the different structural and functional properties of each segment. Each homeotic gene is expressed over a characteristic portion of the embryo. Let's turn now to the homeotic genes and see how their mutation can alter the course of development.

Homeotic mutations produce changes in segment identity

Two bizarre homeotic mutations in Drosophila are the Anten-napedia mutation, in which legs grow in place of antennae (Figure 19.16), and the bithorax mutation, in which an extra pair of wings grows in a thoracic segment (see Figure 21.4a). Edward Lewis at the California Institute of Technology found that Antennapedia and bithorax were mutations not of isolated

Mutated Fruit Fly Body Plan
19.16 A Homeotic Mutation in Drosophila Mutations of the homeotic genes cause body parts to form on inappropriate segments. (a) A wild-type fruit fly. (b) An Antennapedia mutant fruit fly.

genes, but of two adjacent clusters of genes that determine the identity of body segments. Moreover, the genes in these clusters were lined up along the chromosome in the same order as the segments they determined. From left to right, genes in the first cluster specified anterior body segments, starting with genes for the different head segments and ending with thoracic segments. The second cluster began with a gene specifying the last thoracic segment, followed by a gene for the anterior abdominal segments, and ended with a gene for the posterior abdominal segments. Lewis hypothesized that all of these genes might have come from the duplication of a single gene in an ancestral, unsegmented organism.

Molecular biologists confirmed Lewis's hypothesis using nucleic acid hybridization. Several scientists found that a probe for a sequence in one of the genes of one cluster bound not only to its own gene, but also to adjacent genes in its cluster and to genes in the other homeotic cluster. In other words, this DNA sequence is common to all the homeotic genes in both clusters.

Homeobox-containing genes encode transcription factors

The 180-base-pair DNA sequence that is common to the bithorax and Antennapedia gene clusters is called the home-obox. It encodes a 60-amino acid sequence, called the home-odomain, that binds to DNA. The homeodomain turns out to be present in other proteins involved in Drosophila pattern formation, such as Bicoid. In all cases, the homeodomain portion of the protein has a helix-turn-helix motif (see Figure 14.15). Each type of homeodomain recognizes a specific DNA sequence in the promoter of its target genes. The Bicoid homeodomain, for example, recognizes TCCTAATCCC.

What do homeodomain proteins do when they recognize their target sequence in DNA? Not surprisingly, they are transcription factors. The Bicoid protein, for example, binds to promoters of the gap gene hunchback, activating its transcription. The Hunchback protein is also a transcription factor, which binds to enhancers of genes involved in head and thorax formation. In this way, the homeodomain proteins produce the cascade of events that controls Drosophila development.

Homeobox genes are found in many animals, including humans. They play a role in development similar to the role the MADS box genes play in plants. The evolutionary significance of these common pathways for development will be discussed in Chapter 21.

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  • mauri gardemeister
    Which set of genes establishes the body axes?
    5 years ago
  • franziska
    How genes and proteins establish body axis?
    3 years ago

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