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Maternal and Zygotic Segmentation Proteins Regulate Expression of Homeotic (Hox) Genes

As we have just seen, the spatially controlled transcription of pair-rule genes sets up repeating units within the initial sheet of cells composing the early Drosophila embryo. Later, these repeating units must diversify: only some of them will produce appendages, and they will specialize internally as well. This early diversification of body segments depends on the Hox genes, which are important switches that control cell identities and indeed the identities of whole parts of an animal.

Mutations in Hox genes often cause homeosis—that is, the formation of a body part having the characteristics normally found in another part at a different site. For example, flies develop legs on their heads instead of antennae. Loss of function of a particular Hox gene in a location where it is normally active leads to homeosis if a different Hox gene becomes derepressed there; the result is the formation of cells and structures characteristic of the derepressed gene. A Hox gene that is abnormally expressed where it is normally inactive can take over and impose its own favorite developmental pathway on its new location (Figure 15-25).

Hox genes encode highly related transcription factors containing the homeodomain motif. Classical genetic studies in Drosophila led to the discovery of the first Hox genes (e.g., Antennapedia and Ultrabithorax). Corresponding genes with similar functions (orthologs) have since been identified in most animal species. Each Hox gene is transcribed in a particular region along the anterioposterior axis in a remarkable arrangement where the order of genes along the chromosomes is colinear with the order in which they are expressed along the anterior/posterior axis. At one end of the complex are head genes, and genes expressed with progressively more posterior boundaries are in order, wih "tail" genes last. Hox-gene expression domains can overlap (see Figure 15-24). In Drosophila, the spatial pattern of Hox-gene transcription is regulated by maternal, gap, and pair-rule transcription factors. The protein encoded by a particular Hox gene controls the organization of cells within the region in which that Hox gene is expressed. For example, a Hox protein can direct or prevent the local production of a secreted signaling protein, cell-surface receptor, or transcription factor that is needed to build an appendage on a particular body segment.

Drosophila Hox proteins control the transcription of target genes whose encoded proteins determine the diverse morphologies of body segments. Vertebrate Hox proteins similarly control the different morphologies of vertebrae, of repeated segments of the hindbrain, and of the digits of the limbs. The association of Hox proteins with their binding sites on DNA is assisted by cofactors that bind to both Hox proteins and DNA, adding specificity and affinity to these interactions.

When Hox genes are turned on, their transcription must continue to maintain cell properties in specific locations. As in the even-skipped gene, the regulatory regions of some Hox genes contain binding sites for their encoded proteins. Thus Hox proteins can help to maintain their own expression through an autoregulatory loop.

Another mechanism for maintaining normal patterns of Hox-gene expression requires proteins that modulate chro-matin structure. These proteins are encoded by two classes of genes referred to as the Trithorax group and Polycomb group. The pattern of Hox-gene expression is initially normal in Polycomb-group mutants, but eventually Hox-gene transcription is derepressed in places where the genes should be inactive. The result is multiple homeotic transformations. This observation indicates that the normal function of Poly-comb proteins is to keep Hox genes in a transcriptionally inactive state. The results of immunohistological and biochemical studies have shown that Polycomb proteins bind to multiple chromosomal locations and form large complexes containing different proteins of the Polycomb group. The current view is that the transient repression of genes set up by patterning proteins earlier in development is "locked in" by Polycomb proteins. This stable Polycomb-dependent repression may result from the ability of these proteins to assemble inactive chromatin structures (Chapter 11). Poly-comb complexes contain many proteins, including histone

exist. In this case the loss of Ubx function from the third thoracic segment allows wings to form where normally there are only balancer organs called halteres. [From E. B. Lewis, 1978, Nature 276:565; photographs courtesy of E. B. Lewis. Reprinted by permission from Nature, copyright 1978, Macmillan Journals Limited.]

▲ EXPERIMENTAL FIGURE 15-25 Misexpression of the Ultrabithorax (Ubx) gene leads to development of a second pair of wings in Drosophila. Like other Hox genes, Ubx controls the organization of cells within the region in which it is expressed (see Figure 15-24b). Mutations in Hox genes often lead to the formation of a body part where it does not normally exist. In this case the loss of Ubx function from the third thoracic segment allows wings to form where normally there are only balancer organs called halteres. [From E. B. Lewis, 1978, Nature 276:565; photographs courtesy of E. B. Lewis. Reprinted by permission from Nature, copyright 1978, Macmillan Journals Limited.]

deacetylases, and appear to inactivate transcription by modifying histones to promote gene silencing.

Whereas Polycomb proteins repress the expression of certain Hox genes, proteins encoded by the Trithorax group of genes are necessary for maintaining the expression of Hox genes. Like Polycomb proteins, Trithorax proteins bind to multiple chromosomal sites and form large multiprotein complexes, some with a mass of ~2 X 106 Da, about half the size of a ribosome. Some Trithorax-group proteins are homologous to the yeast Swi/Snf proteins, which are crucial for transcriptional activation of many yeast genes. Trithorax proteins stimulate gene expression by selectively remodeling the chromatin structure of certain loci to a transcriptionally active form (see Figure 11-37). The core of each complex is an ATPase, often of the Brm class of proteins. There is evidence that many or most genes require such complexes for transcription to take place.

Flower Development Also Requires Spatially Regulated Production of Transcription Factors

The basic mechanisms controlling development in plants are much like those in Drosophila: differential production of transcription factors, controlled in space and time, specifies cell identities. Our understanding of cell-identity control in plants benefited greatly from the choice of Arabidopsis thaliana as a model organism. This plant has many of the same advantages as flies and worms for use as a model system: it is easy to grow, mutants can be obtained, and transgenic plants can be made. We will focus on certain transcription-control mechanisms regulating the formation of cell identity in flowers. These mechanisms are strikingly similar to those controlling cell-type and antero-posterior regional specification in yeast and animals.

Floral Organs A flower comprises four different organs called sepals, petals, stamens, and carpels, which are arranged in con centric circles called whorls. Whorl 1 is the outermost; whorl 4, the innermost. Arabidopsis has a complete set of floral organs, including four sepals in whorl 1, four petals in whorl 2, six stamens in whorl 3, and two carpels containing ovaries in whorl 4 (Figure 15-26a). These organs grow from a collection of undifferentiated, morphologically indistinguishable cells called the floral meristem. As cells within the center of the floral meristem divide, four concentric rings of primordia form sequentially. The outer-ring primordium, which gives rise to the sepals, forms first, followed by the primordium giving rise to the petals, then the stamen and carpel primordia.

Floral Organ-Identity Genes Genetic studies have shown that normal flower development requires three classes of floral organ-identity genes, designated A, B, and C genes. Mutations in these genes produce phenotypes equivalent to those associated with homeotic mutations in flies and mammals; that is, one part of the body is replaced by another. In plants lacking all A, B, and C function, the floral organs develop as leaves (Figure 15-26b).

Figure 15-27 summarizes the loss-of-function mutations that led to the identification of the A, B, and C gene classes. On the basis of these homeotic phenotypes, scientists proposed a model to explain how three classes of genes control floral-organ identity. According to this ABC model for specifying floral organs, class A genes specify sepal identity in whorl 1 and do not require either class B or class C genes to do so. Similarly, class C genes specify carpel identity in whorl 4 and, again, do so independently of class A and B genes. In contrast with these structures, which are specified by only a single class of genes, the petals in whorl 2 are specified by class A and B genes, and the stamens in whorl 3 are specified by class B and C genes. To account for the observed effects of removing A genes or C genes, the model also postulates that A genes repress C genes in whorls 1 and 2 and, conversely, C genes repress A genes in whorls 3 and 4.

To determine if the actual expression patterns of class A, B, and C genes are consistent with this model, researchers

< EXPERIMENTAL FIGURE 15-26 Mutations in floral organ-identity genes produce homeotic phenotypes.

(a) Flowers of wild-type Arabidopsis thaliana have four sepals in whorl 1, four petals in whorl 2, six stamens in whorl 3, and two carpels in whorl 4.

(b) In Arabidopsis with mutations in all three classes of floral organ-identity genes, the four floral organs are transformed into leaf-like structures. [From D. Weigel and E. M. Meyerowitz, 1994, Cell 78:203; courtesy of E. M. Meyerowitz.]

(a) Wild-type floral organs Sepals (whorl 1)

(a) Wild-type floral organs Sepals (whorl 1)

▲ EXPERIMENTAL FIGURE 15-27 Phenotypic analysis identified three classes of genes that control specification of floral organs in Arabidopsis. (a) Diagram of the arrangement of wild-type floral organs, which are found in concentric whorls. (b) Effect of loss-of-function mutations leading to transformations of one organ into another. Class A mutations affect organ identity

▲ EXPERIMENTAL FIGURE 15-27 Phenotypic analysis identified three classes of genes that control specification of floral organs in Arabidopsis. (a) Diagram of the arrangement of wild-type floral organs, which are found in concentric whorls. (b) Effect of loss-of-function mutations leading to transformations of one organ into another. Class A mutations affect organ identity

(b) Loss-of-function homeotic mutations Whorl

Class A mutants

Class B mutants

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