Genetic Control of Development

The transformation of a single-celled zygote (product of the union between egg and sperm) to a multicellular embryo and then to an adult organism is a complex and amazing process. A fully developed organism has many dif­ferent cell types that serve many different functions. For example, red blood cells carry oxygen, muscle cells contract, fat cells store nutrients, and nerve cells transmit information. In fact, a human has about 350 different types of cells that are distinguishable in both form and function. However, all of the cells of a very early embryo appear to be identical. How, then, do cells become specialized as they divide?

A chicken embryo. During pattern formation, communication between cells of a developing embryo is crucial, so that each cell will “know” its position within the emerging body plan.

Differentiation

The process of cell specialization during development is called differenti­ation. The differentiation process proceeds by the progressive specializa­tion of the protein contents of a cell. Each type of cell in a mature organism has a unique collection of proteins. The blueprints for making these proteins are found in the nucleus of each cell in the form of de­oxyribonucleic acid (DNA). Therefore, the starting place for understand­ing the process of differentiation lies in the nucleus of the original zygote, which contains all of the genetic instructions (DNA) to make all of the cell type repertoire of the mature organism. The original cell is totipo­tent, which means that it can give rise to any cell type. As the embryo de­velops, some cells differentiate, while others, called stem cells, remain pluripotent, which means that they can give rise to a certain subset of cell types called a lineage.

One hypothesis to explain how differentiated cells have a specialized pool of proteins is that differentiating cells retain only the genes (DNA) that encode the proteins they need, and they lose all the other genes. Such a mechanism would produce mature cell types with a different genome. Ex­periments, however, disproved this hypothesis. In 1968, John Gurdon re­moved the nucleus of an unfertilized frog egg and replaced it with the nucleus from a fully differentiated tadpole epithelial cell. The egg developed into a normal tadpole. Gurdon’s classic experiment demonstrated that the nucleus of the differentiated cell still retains the full genome: no genes are lost as a cell’s descendents specialize.

Other experiments supported an alternative hypothesis: that cell spe­cialization reflects the differential regulation of the full set of genes in each cell type. This means that all cells in a mature organism (muscle cells, brain cells) all have the same set of genes, but only a subset of those genes are turned “on” in any specific cell type. Therefore, the process of differentia­tion involves the activation (turning on) of some genes and the inactivation (turning off) of other genes, in order to get the specific collection of pro­teins that characterizes that cell type.

The point during development at which a cell becomes committed to a particular fate is called determination. Differentiation (specialization) is the end product of determination. Determination happens when certain genes are activated or inactivated, and differentiation completes when the cell syn­thesizes all of the tissue-specific proteins that the activated genes encode. For example, when particular cells in a mammalian embryo activate the gene for the protein MyoD and thus begin making MyoD protein, they are de­termined to be muscle cells. As it turns out, the MyoD protein is a tran­scription factor that controls the expression of several other genes. Therefore, MyoD activates and inactivates many of the genes that encode muscle-specific proteins.

What is it, then, that activates MyoD in some cells and not in others during development? Two important types of signals “tell” the developing organism which genes to express and when to express them. Firstly, the un­even distribution of substances (such as messenger RNA, protein, or­ganelles) in the cytoplasm of the unfertilized egg is important to the initial stages of determination. Once the egg is fertilized and the nucleus begins to divide (via mitosis), the resulting nuclei are exposed to different cyto­plasmic surroundings. These different internal environments contain dif­ferent sets of molecules (collectively called cytoplasmic determinants) that regulate the expression of certain genes. Secondly, as the embryo enlarges and increases in cell number, molecules in the extracellular environment can act as signals to developing cells. More often than not, these signal mole­cules are released from other cells in the embryo and affect target cells by regulating the expression of certain genes in those cells. This process is called induction, and is the process by which cells of the embryo commu­nicate and spur on the processes of determination and differentiation. In­duction was discovered in the 1920s by the embryologist Hans Spemann and Hilde Mangold.

Morphogenesis

As cells become specialized they organize into a hierarchy of tissues, organs, and organ systems in which they work as a set, providing a certain function. Morphogenesis is the process by which differentiated cells are organized into these functional groups. In many species, morphogenesis begins before differentiation is completed. For example, in the sea urchin embryo, cells begin to migrate and the embryo changes shape long before the cells are fully differentiated. The process of morphogenesis reflects the differential expression of genes in different cells. The complex interactions of actively differentiating cells actually drive the process of morphogenesis. It is use­ful to look at the gene expression patterns that characterize one compo­nent of morphogenesis.

Pattern Formation

During morphogenesis, a process called pattern formation drives the spa­tial organization of tissues and organs into a defined body plan, or final shape. For example, both dogs and humans have legs made up of bone, mus­cle, and skin. During development, differentiation produces muscle cells, bone cells, and skin cells from an unspecialized set of embryo cells. Mor­phogenesis then organizes the bone cells into bone tissue to form bones and the muscle cells into muscle tissue to form muscles. However, it is the process of pattern formation that organizes those bones and muscles into the spe­cific spatial organization that makes a dog look like a dog and a human look like a human.

The Role of Positional Cues in Pattern Formation. During pattern for­mation, it is crucial for cells of the developing embryo to communicate with one another so that each cell will “know” its relative position within the emerging body plan. The intercellular molecular signals that ultimately drive the process of pattern formation provide positional information. These sig­nals may be chemicals released by certain embryonic cells that diffuse through the embryo and bind to other cells. These diffusible signals are called morphogens. Oftentimes it is the concentration of the morphogen the target cell senses that provides information about the target cell’s prox­imity to the releasing cell.

The development of a chicken wing is a good example of this phenom­enon. During development, the chick wing develops from a structure called the limb bud. Lewis Wolpert discovered a small collection of cells that lie along the rear margin of the limb bud and that specify the position of cells along the front-rear axis of the bud. Ultimately, these cells control the pat­tern of digit development in the wing (chicken digits are like human fin­gers). Wolpert named these cells the polarizing region. They release a morphogen that diffuses through the limb bud. The cells that are exposed to the highest concentration of morphogen (the ones closest to the polar­izing region) develop into a particular digit, the cells that are exposed to an intermediate concentration of morphogen develop into a differently shaped digit, etc. Ultimately the positional cue directs differentiation of the target cell by changing its pattern of gene expression.

The Role of Hox Genes in Pattern Formation. The basic three-dimen­sional layout of an organism is established early in embryonic development. Even an early embryo body has dorsal and ventral axes (top and bottom) as well as anterior and posterior axes (front and back). The differential ex­pression of certain genes in different cells of the embryo controls the emer­gence of this organization. Interestingly, while different types of organisms have dramatically different morphological features, a similar family of genes controls differential gene expression during pattern formation. The Hox family of genes (also called homeotic genes) is found in many different or­ganisms (including plants and animals), and is important in controlling the anatomical identity of different parts of a body along its anterior/posterior axis. Many species have genes that include a nearly identical DNA sequence, called the homeobox region. These genes comprise the Hox family of genes, and they encode proteins that function as transcription factors. In fruit flies, for example, homeotic genes specify the types of appendages that develop on each body segment. The homeotic genes antennal and leg development by regulating the expression of a variety of other genes. The importance of the Hox genes is vividly evident when one of these genes is mutated: the wrong body part forms. For example, mutation in the Antennapedia gene causes fruit flies to develop legs in place of antennae on the head segment.

References

Akam, Michael. “Hox Genes: From Master Genes to Micromanagers.” Current Biol­ogy 8 (1998): R676-R678.

Beardsley, Tim. “Smart Genes.” Scientific American 265 (1991): 86-95.

Fletcher, J. C., and Elliott M. Meyerowitz. “Cell Signaling Within the Shoot Meristem.” Current Opinions in Plant Biology 3 (2000): 23-30.

Gellon, Gabriel, and William McGinnis. “Shaping Animal Body Plans in Develop­ment and Evolution by Modulation of Hox Expression Patterns.” Bioessays 20 (1998): 116-125.

Wolpert, Lewis. “Pattern Formation in Biological Development.” Scientific American 239 (1978): 154-164.

Triumph of the Embryo. Oxford: Oxford University Press, 1991