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Development, Genetic Control of

Development, Genetic Control of

Development is the process through which a multicellular organism arises from a single cell. During development, cells become specialized, or differentiated, taking on different functions and forms. The organism develops a characteristic three-dimensional shape, the parts of which (such as limbs and organs) continue to maintain the same relationship to each other even as the organism grows. How the genes in a single fertilized egg dictate the creation of a complex multicellular creature is the central question in the genetic control of development.

While we are often most curious about human developmental processes, very little is known about the genetics of human development specifically, because experimentation on human embryos is forbidden by law and ethics. Instead, the details of genetic control are best understood in several model organisms, including the roundworm (Caenorhabditis elegans ), the fruit fly (Drosophila melanogaster ), the zebrafish, and the mouse. Each organism differs in the details, and in some cases the overall logic, of genetic control. The understanding of developmental control is not complete for any of these organisms, but scientists have come to understand several mechanisms that contribute to, but do not entirely explain, development.

The Importance of Transcription Factors

With few exceptions, every cell in a multicellular organism contains the same set of genes as every other cell. Despite this genetic equivalence, cells differ greatly in form, function, longevity, and many other characteristics. These differences are due to the differential expression of genes within each cell type. Thus, a nerve cell will express a certain subset of the entire genome , while a gut cell will express a different subset. (To express a gene means to use it to create its encoded product, usually a protein.) Cells become different from one another, therefore, by expressing different sets of genes. Thus, the problem of development can be addressed by understanding how initially identical cells come to express different sets of genes.

The beginning of the answer to this question lies in understanding gene transcription and transcription factors. Transcription is the process in which an enzyme called RNA polymerase binds to a gene to make an RNA copy; this is the first step in expressing the gene. Transcription factors are proteins that bind to regulatory regions of the gene, thereby influencing how easily RNA polymerase attaches to it. Different genes require different sets of transcription factors, and when these factors are in low supply, expression of that gene is slowed or stopped.

Since transcription factors are proteins, they are encoded by their own genes, which are regulated by yet other transcription factors. As we will see, many of the "master" genes that control development encode transcription factors that are expressed early in development. The sequential activation of these genes, in a domino-like fashion, is one way that the overall developmental program is carried out.

The European Way and the American Way

A central question in development is whether a particular cell is predestined to become a specific cell type from the moment of its creation, or whether its fate is less determinate, depending on a variety of cues it receives from its local environment as development proceeds. The developmental geneticist Sydney Brenner dubbed these two alternatives the European way (what matters is who your ancestors are) and the American way (what matters is what your environment is and who your neighbors are). While no multicellular organism displays either alternative exclusively, the roundworm C. elegans operates primarily according to the European plan, with each of its exactly 959 cells largely following a set developmental path, and with few decisions made through interaction with neighboring cells. Drosophila, and mammals such as mice and humans, largely develop according to the American plan, with most cells only gradually taking on a final identity, through repeated communication and competition with neighboring cells.

The difference can be seen in transplant experiments, in which cells of the early embryo are moved from one region to another. In the roundworm, the transplanted cell generally follows its original developmental plan, regardless of the environment in which it finds itself. In fruit flies and mammals, the transplanted cell generally takes on the identity of the region into which it is transplanted, switching from one developmental pathway to another, such as from bone cell to gut cell. This change is not absolute and, most importantly, it is time-dependent. Cells transplanted later in development tend to remain committed to the pathway they were on, despite their new surroundings, leading to the aberrant development of bone cells in the gut, for instance.

Morphogens and Gradients

One problem has intrigued embryologists for many decades: In the absence of strictly defined developmental fates, how does a cell "know" where it is in an embryo, in order to know what to become? An early suggestion, which has been borne out by experiments, is based on the concept of a concentration gradienta variation in concentration of a substance across a region of space.

A concentration gradient is formed whenever a substance is created in one place and moves outward by diffusion. When this occurs, there will be a high concentration of the substance near its point of origin, and increasingly lower concentrations further away. This provides positional information to a cell anywhere along the gradient. Cells pick up this chemical signal, and its strength (concentration) determines the cell's response. Typically, the signal is a transcription factor, and the response is a change in gene transcription.

Because such a signalling substance helps to give form to the embryo, it is termed a morphogen ("morph-" meaning "form," "-gen" meaning "to give rise to"). Morphogen gradients are a key means by which originally identical cells are exposed to different environments and thus sent along different developmental paths. In humans and other mammals, one morphogen that acts early in development is retinoic acid, a relative of vitamin A.

Gradients Determine the Axes of the Fruit Fly Embryo

We can see how such a morphogen acts by considering the development of the anterior-posterior axis in the fruit fly embryo. In the fly egg case, the oocyte, or fertilized egg, is accompanied by "nurse cells" at what will become the head end of the fly. This is called the anterior end; the tail end is posterior. Nurse cells create messenger RNA for a protein called bicoid, which they transport to the oocyte. Because these mRNAs originate in the anterior end, their concentration is highest there, and is lower towards the posterior end. Once the oocyte begins to divide, the mRNA is translated, and the bicoid protein is synthesized. Anterior cells have more of it than posterior cells, and the difference in concentration sets each cell group down its own developmental pathway, with anterior cells developing head structures, and posterior cells tail structures. Note that, in keeping with the "American plan," the fate of each cell is determined not by its ancestry, but by the environment it is in.

The effect of bicoid can be seen in transgenic flies, which have too many or too few copies of the gene. With extra bicoid, a higher-than-normal concentration exists further back in the oocyte, and anterior structures develop further back on the fly. With no bicoid, the anterior structures don't develop at all.

As we might expect, the bicoid protein is a transcription factor , which helps regulate expression of other genes. Other gradients of other transcription factors also exist at this stage, and together, these overlapping gradients establish the dorsal-ventral (back-belly) axis and map out the body segments that characterize all insects. While the details are complex, the fundamental idea is that of combinatorial control: At each position, it is the combination of transcription factors and their concentrations that determines which genes will be expressed, and therefore what the identity of the cells will be.

As segmentation becomes more firmly established and segments begin to take on their unique identities, gradients become less important. Instead, local gene control and cell to cell interactions create the increasingly fine level of spatial patterning.

Homeotic Genes and Segment Identity

Once segmentation is established, another important and remarkable set of genes turns on: the homeotic selector genes. These genes control development within each segment. For instance, the thorax region of the fly contains three segments, each with one pair of legs (the reason insects are six-legged). The homeotic selector gene antennapedia is normally expressed only in the thoracic segments, leading to the creation of a pair of legs.

Note that antennapedia does not itself "code for" legs. Instead, its protein product is a transcription factor. By regulating expression of many other genes, it sets off a cascade of events that results in the creation of legs. Remarkably, however, this single gene is sufficient by itself to turn on the leg-producing program, and its absence keeps the program silent. It can even turn it on in other segments. For instance, when antennapedia is mutated to allow it to be expressed in head segments, a pair of legs develops in place of the normal appendages, antennae (hence the gene name, which means "antenna foot").

Intriguingly, the sequence of homeotic selector genes along the fly chromosome matches the order of segments in which each is expressed. That is, the genes expressed in head segments come first, followed by those expressed in thoracic segments, then the abdomen, then the tail. The way in which this correspondence is exploited during development is still unknown, but the arrangement is clearly not accidental. Related genes have been found in vertebrates, including humans, and the same pattern holds: Genes expressed more anteriorly precede those expressed toward the posterior.

Homeotic Genes in Other Species

Homeotic genes also control development in other species, from yeast to humans, although the details are not as clear as they are for the fruit fly. Homeotic genes, called Hox genes, control the development of segments in the mammalian hindbrain, for example, and help establish the anterior-posterior and dorsal-ventral axes in the limbs. Vertebrates have duplicate copies of the Hox genes on several chromosomes, all of which function together to specify, for example, limb development. The multiple copies provide a redundancy not found in the fruit fly, thus making the effect of individual genes harder to detect. Nonetheless, by "knocking out" multiple versions of a particular Hox gene, researchers have shown their dramatic effects. For example, mice that are missing two copies of Hox 11 have no forelimbs, and the wrist is fused directly to the elbow.

The Homeobox

As transcription factors, the homeotic gene products must bind to DNA. Sequence analysis of both gene and protein has revealed that all share a 180-nucleotide DNA stretch, termed the homeobox, the sequence of which has remained almost unchanged over many millions of years of evolution. It codes for a 60-amino acid long DNA binding region, called the homeodomain. The homeodomain sequence of antennapedia and the mouse homeotic gene Hox B-7 differ by only two amino acids, despite having diverged several hundred million years ago.

Programmed Cell Death: Apoptosis

Development of a multicellular creature requires not only cell differentiation, but in some cases, cell death. Apoptosis helps create the spaces between the fingers, for instance. During brain development, nerve connections are sculpted through the apoptotic death of billions of cells. In C. elegans, exactly 131 cells die by apoptosis.

Cells can be directed to the apoptotic pathway if they fail to receive appropriate signals from their neighbors. In this way, it is thought that cells in the wrong locationa bone cell in the gut, for instancemight be terminated to prevent damage to the organism. The death program itself is carried out within the cell by activation of specific genes that ultimately trigger proteases, which are enzymes that break down cell contents, including the chromosomes.

see also Apoptosis; Fruit Fly: Drosophila ; Roundworm: Caenorhabditis elegans ; Transcription Factors; Transgenic Organisms; Zebrafish.

Richard Robinson

Bibliography

Alberts, Bruce, et al. Molecular Biology of the Cell, 3rd ed. New York: Garland Publishing, 1994.

De Robertis, E. M., G. Oliver, and C. V. Wright. "Homeobox Genes and the Vertebrate Body Plan." Scientific American 263, no. 1 (1990): 46-52.

Gehring, Walter F. Master Control Genes in Development and Evolution. New Haven: Yale University Press, 1998.

Gilbert, Scott F. Developmental Biology, 5th ed. Sunderland, MA: Sinauer Associates, 1997.

Retinoic acid is used as an acne treatment for humans, and must be avoided during pregnancy.

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Genetic Control of Development

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?

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 .


MANGOLD, HILDA (18981924)

German biologist who discovered that a small part of an embryo determines the organization of the entire embryo. When Mangold moved this bit of tissue, called the "primary organizer," in a frog embryo, it developed a second backbone and other organs. Mangold died young in an accident, but her professor, Hans Spemann, received the Nobel prize for their work on the primary organizer.


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 drives the process of morphogenesis. It is useful to look at the gene expression patterns that characterize one component of morphogenesis.


WAELSCH, SALOME (1907 )

German-born U.S. biologist whose work helped lay the foundation for modern genetics. Waelsch overcame anti-Semitism and sexism both in Nazi Germany and later in the United States in her efforts to continue studying the genetics of development in mammals. In 1993, she was awarded the National Medal of Science.


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.

see also Cell Cycle; Control of Gene Expression; Development; Gene; Transcription

Susan T. Rouse

Bibliography

Akam, Michael. "Hox Genes: From Master Genes to Micromanagers." Current Biology 8 (1998): R676R678.

Beardsley, Tim. "Smart Genes." Scientific American 265 (1991): 8695.

Fletcher, J. C., and Elliott M. Meyerowitz. "Cell Signaling Within the Shoot Meristem." Current Opinions in Plant Biology 3 (2000): 2330.

Gellon, Gabriel, and William McGinnis. "Shaping Animal Body Plans in Development and Evolution by Modulation of Hox Expression Patterns." Bioessays 20 (1998): 116125.

Wolpert, Lewis. "Pattern Formation in Biological Development." Scientific American 239 (1978): 154164.

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

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