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 .
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.
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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.
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
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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.