Development of Multicellular Organisms

Development of Multicellular Organisms

https://reasonandscience.catsboard.com/t2759-development-of-multicellular-organisms

Between fertilization and birth, the developing organism is known as an embryo. The concept of an embryo is a staggering one. The development of an embryo starts with a single cell.  The embryo has to respire before it has lungs, digest before it has a gut, build bones when it was pulpy, and form orderly arrays of neurons. One of the critical differences between a developing organism and a machine is that a machine will start to function after it is built. Every multicellular organism has to function even during its development. Multicellular organisms do not spring forth fully formed. Rather, they arise by a relatively slow process of progressive change that we call development. In nearly all cases, the development of a multicellular organism begins with a single cell—the fertilized egg, or zygote, which divides mitotically to produce all the cells of the body. The study of animal development has traditionally been called embryology, after that phase of an organism that exists between fertilization and birth. But development does not stop at birth, or even at adulthood. Most organisms never stop developing. Each day we replace more than a gram of skin cells (the older cells being sloughed off as we move), and our bone marrow sustains the development of millions of new red blood cells every minute of our lives. Some animals can regenerate severed parts, and many species undergo metamorphosis (such as the transformation of a tadpole into a frog, or a caterpillar into a butterfly).

Development accomplishes two major objectives. First, it generates cellular diversity and order within the individual organism; second, it ensures the continuity of life from one generation to the next. Put another way, there are two fundamental questions in developmental biology. How does the fertilized egg give rise to the adult body? And, how does that adult body produce yet another body? These huge questions can be subdivided into several categories of questions scrutinized by developmental biologists:

The question of differentiation 
A single cell, the fertilized egg, gives rise to hundreds of different cell types—muscle cells, epidermal cells, neurons, lens cells, lymphocytes, blood cells, fat cells, and so on. This generation of cellular diversity is called differentiation. Since every cell of the body (with very few exceptions) contains the same set of genes, how can this identical set of genetic instructions produce different types of cells? How can a single fertilized egg cell generate so many different cell types?1
The question of morphogenesis 
How can the cells in our body organize into functional structures? Our differentiated cells are not randomly distributed. Rather, they are organized into intricate tissues and organs. During development, cells divide, migrate, and die; tissues fold and separate. Our fingers are always at the tips of our hands, never in the middle; our eyes are always in our heads, not in our toes or gut. This creation of ordered form is called morphogenesis, and it involves coordinating cell growth, cell migration, and cell death.
The question of growth
 If each cell in our face were to undergo just one more cell division, we would be considered horribly malformed. If each cell in our arms underwent just one more round of cell division, we could tie our shoelaces without bending over. How do our cells know when to stop dividing? Our arms are generally the same size on both sides of the body. How is cell division so tightly regulated?
The question of reproduction
 The sperm and egg are highly specialized cells, and only they can transmit the instructions for making an organism from one generation to the next. How are these germ cells set apart, and what are the instructions in the nucleus and cytoplasm that allow them to form the next generation?
The question of regeneration 
Some organisms can regenerate every part of their bodies. Some salamanders regenerate their eyes and their legs, while many reptiles can regenerate their tails. While mammals are generally poor at regeneration, there are some cells in our bodies—stem cells—that are able to form new structures even in adults. How do stem cells retain this capacity, and can we harness it to cure debilitating diseases?
The question of environmental integration 
The development of many (perhaps all) organisms is influenced by cues from the environment that surrounds the embryo or larva. The sex of many species of turtles, for instance, depends on the temperature the embryo experiences while in the egg. The formation of the reproductive system in some insects depends on bacteria that are transmitted inside the egg. Moreover, certain chemicals in the environment can disrupt normal development, causing malformations in the adult. How is the development of an organism integrated into the larger context of its habitat?
The question of evolution 
Evolution involves inherited changes of development. When we say that today’s one-toed horse had a five-toed ancestor, we are saying that changes in the development of cartilage and muscles occurred over many generations in the embryos of the horse’s ancestors. How do changes in development create new body forms? Which heritable changes are possible, given the constraints imposed by the necessity of the organism to survive as it develops?

The questions asked by developmental biologists have become critical in molecular biology, physiology, cell biology, genetics, anatomy, cancer research, neurobiology, immunology, ecology, and evolutionary biology. The study of development has become essential for understanding all other areas of biology. In turn, the many advances of molecular biology, along with new techniques of cell imaging, have finally made these questions answerable. This is exciting; for, as the Nobel-prize winning developmental biologist Hans Spemann stated in 1927, “We stand in the presence of riddles, but not without the hope of solving them. And riddles with the hope of solution—what more can a scientist desire?” So, we come bearing questions. They are questions bequeathed to us by earlier generations of biologists, philosophers, and parents. They are questions with their own histories, questions discussed on an anatomical level by people such as Aristotle, William Harvey, St. Albertus Magnus, and Charles Darwin. More recently, these questions have been addressed on the cellular and molecular levels by men and women throughout the world, each of whom brings to the laboratory his or her own perspectives and training. For there is no one way to become a developmental biologist, and the field has benefitted by having researchers trained in cell biology, genetics, biochemistry, immunology, and even anthropology, engineering, physics, and art.

The Cycle of Life
For animals, fungi, and plants, the sole way of getting from egg to adult is by developing an embryo. The embryo is where genotype is translated into phenotype, where inherited genes are expressed to form the adult. The developmental biologist usually finds the transient stages leading up to the adult to be the most interesting. Developmental biology studies the building of organisms. It is a science of becoming, a science of process. One of the major triumphs of descriptive embryology was the idea of a generalizable animal life cycle. Modern developmental biology investigates the temporal changes of gene expression and anatomical organization along this life cycle. Each animal, whether earthworm or eagle, termite or beagle, passes through similar stages of development: fertilization, cleavage, gastrulation, organogenesis, birth, metamorphosis, and gametogenesis. The stages of development between fertilization and hatching (or birth) are collectively called embryogenesis.

1. Fertilization involves the fusion of the mature sex cells, the sperm and egg, which are collectively called the gametes. The fusion of the gamete cells stimulates the egg to begin development and initiates a new individual. The subsequent fusion of the gamete nuclei (the male and female pronuclei, each of which has only half the normal number of chromosomes characteristic for the species) gives the embryo its genome, the collection of genes that helps instruct the embryo to develop in a manner very similar to that of its parents.
2. Cleavage is a series of extremely rapid mitotic divisions that immediately follow fertilization. During cleavage, the enormous volume of zygote cytoplasm is divided into numerous smaller cells called blastomeres. By the end of cleavage, the blastomeres have usually formed a sphere, known as a blastula.
3. After the rate of mitotic division slows down, the blastomeres undergo dramatic movements and change their positions relative to one another. This series of extensive cell rearrangements is called gastrulation, and the embryo is said to be in the gastrula stage. As a result of gastrulation, the embryo contains three germ layers (endoderm, ectoderm, and mesoderm) that will interact to generate the organs of the body.
4. Once the germ layers are established, the cells interact with one another and rearrange themselves to produce tissues and organs. This process is called organogenesis. Chemical signals are exchanged between the cells of the germ layers, resulting in the formation of specific organs at specific sites. Certain cells will undergo long migrations from their place of origin to their final location. These migrating cells include the precursors of blood cells, lymph cells, pigment cells, and gametes (eggs and sperm).
5. In many species, the organism that hatches from the egg or is born into the world is not sexually mature. Rather, the organism needs to undergo metamorphosis to become a sexually mature adult. In most animals, the young organism is a called a larva, and it may look significantly different from the adult. In many species, the larval stage is the one that lasts the longest, and is used for feeding or dispersal. In such species, the adult is a brief stage whose sole purpose is to reproduce. In silkworm moths, for instance, the adults do not have mouthparts and cannot feed; the larva must eat enough so that the adult has the stored energy to survive and mate. Indeed, most female moths mate as soon as they eclose from the pupa, and they fly only once—to lay their eggs. Then they die.
6. In many species, a group of cells is set aside to produce the next generation (rather than forming the current embryo). These cells are the precursors of the gametes. The gametes and their precursor cells are collectively called germ cells, and they are set aside for reproductive function. All other cells of the body are called somatic cells. This separation of somatic cells (which give rise to the individual body) and germ cells (which contribute to the formation of a new generation) is often one of the first differentiation to occur during animal development. The germ cells eventually migrate to the gonads, where they differentiate into gametes. The development of gametes, called gametogenesis, is usually not completed until the organism has become physically mature. At maturity, the gametes may be released and participate in fertilization to begin a new embryo. The adult organism eventually undergoes senescence and dies, its nutrients often supporting the early embryogenesis of its offspring and its absence allowing less competition. Thus, the cycle of life is renewed.

An Overview of Early Development
Cells in the cleavage-stage cells are called blastomeres.In most species (mammals being the chief exception), both the initial rate of cell division and the placement of the blastomeres with respect to one another are under the control of proteins and mRNAs stored in the oocyte. Only later do the rates of cell division and the placement of cells come under the control of the newly formed organism’s own genome. During the initial phase of
development, when cleavage rhythms are controlled by maternal factors, cytoplasmic volume does not increase. Rather, the zygote cytoplasm is divided into increasingly smaller cells—first in half, then quarters, then eighths, and so forth. Cleavage occurs very rapidly in most invertebrates, probably as an adaptation to generate a large number of cells quickly and to restore the somatic ratio of nuclear volume to cytoplasmic volume. The embryo often accomplishes this by abolishing the gap periods of the cell cycle (the G1 and G2 phases), when growth can occur. A frog egg, for example, can divide into 37,000 cells in just 43 hours. Mitosis in cleavage-stage Drosophila embryos occurs every 10 minutes for more than 2 hours, forming some 50,000 cells in just 12 hours. The pattern of embryonic cleavage peculiar to a species is determined by two major parameters: 

(1) the amount and distribution of yolk protein within the cytoplasm, which determine where cleavage can occur and the relative sizes of the blastomeres; and 
(2) factors in the egg cytoplasm that influence the angle of the mitotic spindle and the timing of its formation.

Cell cleavage is accomplished by a remarkable coordination between the cytoskeleton and the chromosomes. This integration of part and whole is becoming better understood as better imaging technologies become available.



Above provides a classification of cleavage types and shows the influence of yolk on cleavage symmetry and pattern.

Gastrulation: “The most important time in your life”
According to embryologist Lewis Wolpert (1986), “It is not birth, marriage, or death, but gastrulation which is truly the most important time in your life.” This is not an overstatement. Gastrulation is what makes animals animals. (Animals gastrulate; plants and fungi do not.) During gastrulation, the cells of the blastula are given new positions and new neighbours and the multilayered body plan of the organism is established. The cells that will form the endodermal and mesodermal organs are brought to the inside of the embryo, while the cells that will form the skin and nervous system are spread over its outside surface. Thus, the three germ layers—outer ectoderm, inner endoderm, and interstitial mesoderm—are first produced during gastrulation. In addition, the stage is set for the interactions of these newly positioned tissues.

Gastrulation usually proceeds by some combination of several types of movements. These movements involve the entire embryo, and cell migrations in one part of the gastrulating embryo must be intimately coordinated with other movements that are taking place simultaneously. Although patterns of gastrulation vary enormously throughout the animal kingdom, all of the patterns are different combinations of the five basic types of cell movements—invagination, involution, ingression, delamination, and epiboly. 

In addition to establishing which cells will be in which germ layer, embryos must develop three crucial axes that are the foundation of the body: the anterior-posterior axis, the dorsal-ventral axis, and the right-left axis. 

The embryo is organized into germ layers—three distinct regions of the embryo that give rise to the differentiated cells types and specific organ systems. 


The dividing cells of the fertilized egg form three distinct embryonic germ layers. Each of the germ layers gives rise to myriad differentiated cell types (only a few representatives are shown here) and distinct organ systems.
The germ cells (precursors of the sperm and egg) are set aside early in development and do not arise from any particular germ layer.

These three layers are found in the embryos of most animal phyla:
The ectoderm generates the outer layer of the embryo. It produces the surface layer (epidermis) of the skin and forms the brain and nervous system.
The endoderm becomes the innermost layer of the embryo and produces the epithelium of the digestive tube and its associated organs (including the lungs).
The mesoderm becomes sandwiched between the ectoderm and endoderm. It generates the blood, heart, kidney, gonads, bones, muscles, and connective tissues.

Each of the three germ layers generally gives rise to the same organs, whether the organism is a fish, a frog, or a chick. The notochord is the rod of mesoderm that separates the embryo into right and left halves and instructs the ectoderm above it to become the nervous system


Two types of microscopy are used to visualize the notochord and its separation of vertebrate embryos (in this case a chick) into right and left halves. 
The notochord instructs the ectoderm above it to become the nervous system (the neural tube at this stage of development). To either side of the notochord and the neural tube are the mesodermal masses called somites, which will form vertebrae, ribs, and skeletal muscles. (A) Fluorescence micrograph stained with different dyes to highlight nuclear DNA (blue), cytoskeletal microtubules (red, yellow), and the extracellular matrix (green). (B) Scanning electron micrograph of the same stage, highlighting the three-dimensional relationship of the structures.

Keeping track of moving cells: fate maps and cell lineages
There are two major types of cells in the embryo: epithelial cells, which are tightly connected to one another in sheets or tubes; and mesenchymal cells, which are unconnected or loosely connected to one another and can operate as independent units. Within these two types of arrangements, morphogenesis is brought about through a limited repertoire of variations in cellular processes:
• Direction and number of cell divisions. Think of the faces of two dog breeds— say, a German shepherd and a poodle. The faces are made from the same cell types, but the number and orientation of the cell divisions are different. Think also of the legs of a German shepherd compared with those of a dachshund. The skeleton-forming cells of the dachshund have undergone fewer cell divisions than those of taller dogs.
• Cell shape changes. Cell shape change is a critical feature of development. Changing the shapes of epithelial cells often creates tubes out of sheets (as when the neural tube forms), and a shape change from epithelial to mesenchymal is critical when individual cells migrate away from the epithelial sheet (as when muscle cells are formed). 
• Cell migration. Cells have to move in order to get to their appropriate locations. The germ cells have to migrate into the developing gonad, and the primordial heart cells meet in the middle of the vertebrate neck and then migrate to the left part of the chest.
• Cell growth. Cells can change in size. This is most apparent in the germ cells: the sperm eliminates most of its cytoplasm and becomes smaller, whereas the developing egg conserves and adds cytoplasm, becoming comparatively huge. Many cells undergo an “asymmetric” cell division that produces one big cell and one small cell, each of which may have a completely different fate.
• Cell death. Death is a critical part of life. The embryonic cells that constitute the webbing between our toes and fingers die before we are born. So do the cells of our tails. The orifices of our mouth, anus, and reproductive glands all form through apoptosis—the programmed death of certain cells at particular times and places.
• Changes in the composition of the cell membrane or secreted products. Cell membranes and secreted cell products influence the behavior of neighboring cells. For instance, extracellular matrices secreted by one set of cells will allow the migration of their neighboring cells. Extracellular matrices made by other cell types will prohibit the migration of the same set of cells. In this way, “paths and guiderails” are established for migrating cells.

An animal or plant starts its life as a single cell—a fertilized egg, or zygote. During development, this cell divides repeatedly to produce many different kinds of cells, arranged in a final pattern of spectacular complexity and precision. The goal of developmental cell biology is to understand the cellular and molecular mechanisms that direct this amazing transformation. Plants and animals have very different ways of life, and they use different
developmental strategies. Four processes are fundamental to animal development: 

(1) cell proliferation, which produces many cells from one; 
(2) cell-cell interactions, which coordinate the behaviour of each cell with that of its neighbours; 
(3) cell specialization, or differentiation, which creates cells with different characteristics at different positions; and 
(4) cell movement, which rearranges the cells to form structured tissues and organs

In a developing animal embryo, the four fundamental processes are happening in a kaleidoscopic variety of ways, as they give rise to different parts of the organism. Like the members of an orchestra, the cells in the embryo have to play their individual parts in a highly coordinated manner. In the embryo, however, there is no conductor—no central authority—to direct the performance. Instead, development is a self-assembly process in which the cells, as they grow and proliferate, organize themselves into increasingly complex structures. Each of the millions of cells has to choose for itself how to behave, selectively utilizing the genetic instructions in its chromosomes.

At each stage in its development, the cell is presented with a limited set of options, so that its developmental pathway branches repeatedly, reflecting a large set of sequential choices. Like the decisions we make in our own lives, the choices made by the cell are based on its internal state—which largely reflects its history— and on current influences from other cells, especially its close neighbours. To understand development, we need to know how each choice is controlled and how it depends on previous choices. Beyond that, we need to understand how the choices, once made, influence the cell’s chemistry and behaviour, and how cell behaviours act synergistically to determine the structure and function of the body. As cells become specialized they change not only their chemistry but also their shape and their attachments to other cells and to the extracellular matrix. They move and rearrange themselves to create the complex architecture of the body, with all its tissues and organs, each structured precisely and defined in size. To understand this process of form generation, or morphogenesis, we will need to take account of the mechanical, as well as the biochemical, interactions between the cells.

At first glance, one would no more expect the worm, the flea, the eagle, and the giant squid all to be generated by the same developmental mechanisms than one would suppose that the same methods were used to make a shoe and an airplane. Remarkably, however, research in the past 30 years has revealed that much of the basic machinery of development is essentially the same in all animals—not just in all vertebrates, but in all the major phyla of invertebrates too. Recognizably similar, related molecules define the specialized animal cell types, mark the differences between body regions, and help create the animal body pattern. Homologous proteins are often functionally interchangeable between very different species. Thus, a human protein produced artificially in a fly, for example, can perform the same function as the fly’s own version of that protein.

Animals live by eating other organisms. Thus, despite their remarkable diversity, animals as different as worms, molluscs, insects, and vertebrates share anatomical features that are fundamental to this way of life. Epidermal cells form a protective outer layer; gut cells absorb nutrients from ingested food; muscle cells allow movement, and neurons and sensory cells control behaviour. These diverse cell types are organized into tissues and organs, forming a sheet of skin covering the exterior, a mouth for feeding, and an internal gut tube to digest food—with muscles, nerves, and other tissues arranged in the space between the skin and the gut tube. Many animals have clearly defined axes—an anteroposterior axis, with mouth and brain anterior and anus posterior; a dorsoventral axis, with back dorsal and belly ventral; and a left-right axis.

The shared anatomical features of animals develop through conserved mechanisms. After fertilization, the zygote usually divides rapidly, or cleaves, to form many smaller cells; during this cleavage, the embryo, which cannot yet feed, does not grow. This phase of development is initially driven and controlled entirely by the material deposited in the egg by the mother. The embryonic genome remains inactive until a point is reached when maternal mRNAs and proteins rather abruptly begin to be degraded. The embryo’s genome is activated, and the cells cohere to form a blastula—typically a solid or a hollow fluid-filled ball of cells. Complex cell rearrangements called gastrulation (from the Greek “gaster,” meaning “belly”) then transform the blastula into a multilayered structure containing a rudimentary internal gut


The early stages of development, as exemplified by a frog.
(A) A fertilized egg divides to produce a blastula—a sheet of epithelial cells often surrounding a cavity. During gastrulation, some of the cells tuck into the interior to form the mesoderm (green) and endoderm (yellow). Ectodermal cells (blue) remain on the outside. 
(B) A cross-section through the trunk of an amphibian embryo shows the basic animal body plan, with a sheet of ectoderm on the outside, a tube of endoderm on the inside, and mesoderm sandwiched between them. The endoderm forms the epithelial lining of the gut, from the mouth to the anus. It gives rise not only to the pharynx, esophagus, stomach, and intestines, but also to many associated structures. The salivary glands, liver, pancreas, trachea, and lungs, for example, all develop from the wall of the digestive tract and grow to become systems of branching tubes that open into the gut or pharynx. The endoderm forms only the epithelial components of these structures— the lining of the gut and the secretory cells of the pancreas, for example. The supporting muscular and fibrous elements arise from the mesoderm. The mesoderm gives rise to the connective tissues—at first, to the loose mesh of cells in the embryo known as mesenchyme, and ultimately to cartilage, bone, and fibrous tissue, including the dermis (the inner layer of the skin). The mesoderm also forms the muscles, the entire vascular system—including the heart, blood vessels, and blood cells—and the tubules, ducts, and supporting tissues of the kidneys and gonads. The notochord forms from the mesoderm and serves as the core of the future backbone and the source of signals that coordinate the development of surrounding tissues. The ectoderm will form the epidermis(the outer, epithelial layer of the skin) and epidermal appendages such as hair, sweat glands, and mammary glands. It will also give rise to the whole of the nervous system, central and peripheral, including not only neurons and glia but also the sensory cells of the nose, the ear, the eye, and other sense organs.

Some cells of the blastula remain external, constituting the ectoderm, which will give rise to the epidermis and the nervous system; other cells invaginate, forming the endoderm, which will give rise to the gut tube and its appendages, such as lung, pancreas, and liver. Another group of cells moves into the space between ectoderm and endoderm and forms the mesoderm, which will give rise to muscles, connective tissues, blood, kidney, and various other components. Further cell movements and accompanying cell differentiations create and refine the embryo’s architecture. The ectoderm, mesoderm, and endoderm formed during gastrulation constitute the three germ layers of the early embryo. Many later developmental transformations will produce the elaborately structured organs. But the basic body plan and axes set up in miniature during gastrulation are preserved into adult life, when the organism may be billions of times larger.

Concomitant with the refinement of the body plan, the individual cells become more and more restricted in their developmental potential. During the blastula stages, cells are often totipotent or pluripotent—they have the potential to give rise to all or almost all of the cell types of the adult body. The pluripotency is lost as gastrulation proceeds: a cell located in the endodermal germ layer, for example, can give rise to the cell types that will line the gut or form gut-derived organs such as the liver or pancreas, but it no longer has the potential to form mesoderm-derived structures such as skeleton, heart, or kidney. Such a cell is said to be determined for an endodermal fate. Thus, cell determination starts early and progressively narrows the options as the cell steps through a programmed series of intermediate states—guided at each step by its genome, its history, and its interactions with neighbours. The process reaches its limit when a cell undergoes terminal differentiation to form one of the highly specialized cell types of the adult body. Although there are cell types in the adult that retain some degree of pluripotency, their range of options is generally narrow.



The lineage from blastomere to differentiated cell type.
As development proceeds, cells become more and more specialized. Blastomeres have the potential to give rise to most or all cell types. Under the influence of signalling molecules and gene regulatory factors, cells acquire more restricted fates until they differentiate into highly specialized cell types, such as the pancreatic β-islet cells that secrete the hormone insulin.

Genes involved in Cell-Cell communication and transcriptional control are especially important for animal development
What are the genes that animals share with one another but not with other kingdoms of life? These would be expected to include genes required specifically for animal development but not needed for unicellular existence. Comparison of animal genomes with the genome of budding yeast—a unicellular eukaryote— suggests that three classes of genes are especially important for multicellular organization.

The first class includes genes that encode proteins used for cell–cell adhesion and cell signaling; hundreds of human genes encode signal proteins, cell-surface receptors, cell adhesion proteins, or ion channels that are either not present in yeast or present in much smaller numbers.

The second class includes genes encoding proteins that regulate transcription and chromatin structure: more than 1000 human genes encode transcription regulators, but only about 250 yeast genes do so. The development of animals is dominated by cell–cell interactions and by differential gene expression.

The third class of noncoding RNAs has a more uncertain status: it includes genes that encode microRNAs (miRNAs); there are at least 500 of these in humans. Along with the regulatory proteins, they play a significant part in controlling gene expression during animal development, but the full extent of their importance is still unclear.

The loss of individual miRNA genes in C. elegans, where their functions have been well studied, rarely leads to obvious phenotypes, suggesting that the roles of miRNAs during animal development are often subtle, serving to fine-tune the developmental machinery rather than to form its core structures.

Each gene in a multicellular organism is associated with many thousands of nucleotides of noncoding DNA that contains regulatory elements. These regulatory elements determine when, where, and how strongly the gene is to be expressed, according to the transcription regulators and chromatin structures that are present in the particular cell.


Regulatory DNA defines the gene expression patterns in development. 
The genome is the same in a muscle cell as in a skin cell, but different genes are active because these cells express different transcription regulators that bind to gene regulatory elements. For example, transcription regulators in skin cells recognize a regulatory element in gene 1, leading to its activation, whereas a different set of regulators is present in muscle cells, binding to and activating gene 3. Transcriptional regulators that activate the expression of gene 2 are present in both cell types.

A change in the regulatory DNA, even without any change in the coding DNA, can alter the logic of the gene-regulatory network and change the outcome of development. When we compare the genomes of different animal species, we find a coding and regulatory DNA to different extents. Changes in regulatory DNA are largely responsible for the dramatic differences between one class of animals and another. We can view the protein products of the coding sequences as a conserved kit of common molecular parts, and the regulatory DNA as instructions for assembly: with different instructions, the same kit of parts can be used to make a whole variety of different body structures. 

Small numbers of Cell-Cell signalling pathways coordinate spatial patterning
Spatial patterning of a developing animal requires that cells become different according to their positions in the embryo, which means that cells must respond to extracellular signals produced by other cells, especially their neighbours. In what is probably the commonest mode of spatial patterning, a group of cells starts out with the same developmental potential, and a signal from cells outside the group then induces one or more members of the group to change their character. This process is called inductive signalling. Generally, the inductive signal is limited in time and space so that only a subset of the cells capable of responding—the cells close to the source of the signal—take on the induced character. Some inductive signals depend on cell–cell contact; others act over a longer range and are mediated by molecules that diffuse through the extracellular medium or are transported in the bloodstream. Most of the known inductive events in animal development are governed by a small number of highly conserved signaling pathways, including 

- transforming growth factor-β (TGFβ), 
- Wnt, 
- Hedgehog, 
- Notch, and 
- receptor tyrosine kinase (RTK) pathways. 

The discovery of the limited vocabulary that developing cells use for intercellular communication has emerged over the past 25 years as one of the great simplifying features of developmental biology. But how can this small number of signalling pathways generate the huge diversity of cells and patterns? Three kinds of mechanisms are responsible. First, through gene duplication, the basic components of a pathway often come to be encoded by small families of closely related homologous genes. This allows for diversity in the operation of the pathway, according to which family member is employed in a given situation. Notch signalling, for example, may be mediated by Notch1 in one tissue, but by its homolog Notch4 in another. Second, the response of a cell to a given signal protein depends on the other signals that the cell is receiving concurrently As a result, different combinations of signals can generate a large variety of different responses. Third, and most fundamental, the effect of activating a signalling pathway depends on the previous experiences of the responding cell: past influences leave a lasting mark, registered in the state of the cell’s chromatin and the selection of transcription regulatory proteins and RNA molecules that the cell contains. This cell memory enables cells with different histories to respond to the same signals differently. Thus, the same few signalling pathways can be used repeatedly at different times and places with different outcomes, so as to generate patterns of unlimited complexity.

Morphogens are long-range inductive signals that exert graded effects
Signal molecules often govern simple yes–no choices—one outcome when their concentration is high, another when it is low. In many cases, however, the responses are more finely graded: a high concentration of a signal molecule may, for example, direct cells into one developmental pathway, an intermediate concentration into another, and a low concentration into yet another. One common way to generate such different concentrations of a signal molecule is for the molecule to diffuse out from a localized signaling source, creating a concentration gradient. Cells at different distances from the source are driven to behave in a variety of different ways, according to the signal concentration that they experience. A signal molecule that imposes a pattern on a whole field of cells in this way is called a morphogen. In the simplest case, a specialized group of cells produces a morphogen at a steady rate, and the morphogen is then degraded as it diffuses away from this source. The speed of diffusion and the half-life of the morphogen will together determine the range and steepness of its resulting gradient Morphogen gradients, and other kinds of inductive signal, exploit an existing asymmetry in the embryo to create further asymmetries and differences between cells: already, at the outset, some cells are specialized to produce the morphogen and thereby impose a pattern on another class of cells that are sensitive to it. But what if there is no clear initial asymmetry? Can a regular pattern arise spontaneously within a set of cells that are initially all alike? The answer is yes. The fundamental principle underlying such de novo pattern formation is positive feedback: cells can exchange signals in such a way that any small initial discrepancy between cells at different sites becomes self-amplifying,
driving the cells toward different fates.

Asymmetric cell division can also generate diversity
Cell diversification does not always depend on extracellular signals: in some cases, daughter cells are born different as a result of an asymmetric cell division, in which some important molecule or molecules are distributed unequally between the two daughters. This asymmetric inheritance ensures that the two daughter cells develop differently. 


Two ways of making sister cells different.

Asymmetric division is a common feature of early development, where the fertilized egg already has an internal pattern and cleavage of this large cell segregates different determinants into separate blastomeres.  Asymmetric division also plays a part in some later developmental processes.

Initial patterns are established in small fields of cells and refined by sequential induction as the embryo grows

The signals that organize the spatial pattern of cells in an embryo generally act over short distances and govern relatively simple choices. A morphogen, for example, typically acts over a distance of less than 1 mm—an effective range for diffusion —and directs choices between several developmental options for the cells on which it acts. Yet the organs that eventually develop are much larger and more complex than this. The cell proliferation that follows the initial specification accounts for the size increase, while the refinement of the initial pattern is explained by a series of local inductions plus other interactions that add successive levels of detail on an initially simple sketch. For example, as soon as two types of cells are present in a developing tissue, one of them can produce a signal that induces a subset of the neighbouring cells to specialize in a third way. The third cell type can in turn signal back to the other two cell types nearby, generating a fourth and a fifth cell type, and so on 


Patterning by sequential induction. 
A series of inductive interactions can generate many types of cells, starting from only a few

This strategy for generating a progressively more complicated pattern is called sequential induction. It is chiefly through sequential inductions that the body plan of a developing animal, after being first roughed out in miniature, becomes elaborated with finer and finer details as development proceeds.



Alberts, Molecular biology of the Cell , 6th ed. page 1145