Gene Switches

All animals, including you and me, begin as a single egg. Once fertilized, that egg becomes many different kinds of cells. Here we see just two examples, heart cells (far left) and nerve cells, or neurons. Altogether, multicellular organisms like humans have thousands of differentiated cells. Each is optimized for use in the brain, the liver, the skin, and so on. Remarkably, the DNA inside all these cells is exactly the same. What makes the cells differ from one another is that different genes in that DNA are either turned on or off in each type of cell.

Take a typical cell, such as a red blood cell. Each gene within that cell has a coding region. This region encodes the information used to make a particular protein, such as the hemoglobin in the red blood cells seen here. (Hemoglobin shuttles oxygen to the tissues and carbon dioxide back out to the lungs—or gills, if you're a fish.) But another region of the gene, called "regulatory DNA," determines whether and when the gene will be expressed, or turned on, in a particular kind of cell. If you're a brain cell, for instance, you wouldn't want the genes encoding hemoglobin proteins to be transcribed. This precise transcribing of genes is handled by proteins known as transcription factors, which bind to the regulatory DNA, thereby generating instructions for the coding region.

One important class of transcription factors is encoded by the so-called homeotic, or Hox, genes. Found in all animals, Hox genes act to "regionalize" the body along the embryo's anterior-to-posterior (head-to-tail) axis. In a fruit fly, for example, Hox genes lay out the various main body segments—the head, thorax, and abdomen. Here we see a representation of a fruit fly embryo viewed from the side, with its anterior end to the left and with various Hox genes shown in different colors. Each Hox gene, such as the blue Ultrabithorax or Ubx gene, is expressed in different areas, or domains, along the anterior-to-posterior axis. The arced, colored bars give an idea of the full range, or domain, of each gene's expression.

Amazingly, all animals, from fruit flies to mice to people, rely on the same basic Hox-gene complex. Here we see a graphic of a mouse embryo viewed, again, from the side, with its anterior end to the left and its various Hox genes indicated above. If you compare this illustration with that of the fruit fly in the previous entry, you'll see how the same Hox genes used to encode the segments of the fly encode the brain and spinal cord as well as the spinal column of the mouse. The colored bars indicate each gene's expression domain in the brain and spinal cord, while the colored ovals show each gene's expression domain in the spinal column. (The purple ovals mark the expression domain of the Hox10 gene, which, along with Hox genes 11 through 13, is not found in the fruit fly and thus is not shown here.)

Using different-colored antibody stains, we can see exactly where and to what degree Hox genes are expressed. This is a photograph of a fly embryo, once again with its anterior end to the left. It shows the expression pattern of four different Hox genes—Scr (black), Antp (red), Ubx (blue), and Abd-B (brown). As you can see, each Hox gene is expressed in a specific region along the anterior-to-posterior axis of the embryo. Now have a look at what results from such expression in the mature animal.

A fly's body has three main divisions: head, thorax, and abdomen. We'll focus on the thorax, which itself has three main segments. In a normal adult fly, the second thoracic segment features a pair of wings, while the third thoracic segment has a pair of small, balloon-shaped structures called halteres (see arrow in inset). A modified second wing, the haltere serves as a flight stabilizer. In order for the pair of wings and the pair of halteres (as well as all other parts of the fly) to develop properly, the fly's suite of Hox genes must be expressed in a precise way and at precise times.

During development, the fly's two wings grow from a structure in the larva known as the wing imaginal disk (top images at left). (An imago is an insect in its final, adult state.) The haltere grows from the larval haltere imaginal disk (bottom images at left). Remember the Ubx Hox gene? Using staining again, we can detect the gene product of Ubx. This reveals that the Ubx gene is naturally "off" in the wing disk—note the absence of the bright green stain in the upper right image—and is "on" in the haltere disk (lower right image). Now you'll see what happens when the Ubx gene—just one of a large number of Hox genes—is turned off in the haltere disk.

In the fly seen here, a genetic mutation caused the Ubx gene to be turned off, during the larval stage, in the third thoracic segment. This is the segment that normally produces the haltere. Notice anything different? Instead of a pair of halteres, the fly has a second set of wings. With the switch of that single Hox gene, Ubx, from on to off, the third thoracic segment became an additional second thoracic segment and the pair of halteres became a second pair of wings. This illustrates the remarkable ability of transcription factors like Ubx to control patterning as well as cell type during development.

Gene switches such as Ubx make the initial decisions of which genes to turn on or off in different body regions and cell types. Later in an animal's development, epigenetic switches take over. These epigenetic mechanisms act to maintain the fate of cells by doing what the Hox genes and other transcription factors did earlier, namely, controlling the "on" and "off" state of genes within each cell. This highly evolved, highly orchestrated ability to make genes active or inactive—both genetically and epigenetically—is the key to the success of multicellular plants and animals, including the most complex and mysterious of all, us.