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164 Morphogenesis and Differentiation in Animal Development

Every embryo undergoes a series of stages wherein cells divide, migrate, and differentiate into the 's adult form. Each performs a specific role in the body, serving as a component of a particular organ system. An immature cell can differentiate into part of the skeletal system or digestive system, depending on the signals that direct its maturation process. How do cells know what to do during development? Why do some cells move to a certain area of the developing body and not to another area? The terms morphogenesis and differentiation encompass these developmental processes, including directing cells to move towards specific areas and inducing these cells to mature into fully functional, specialized cells that the body needs to survive.

Morphogenesis and Differentiation During Animal Development In very broad terms, two forces influence the migration and maturation of cells during morphogenesis. One involves cytoplasmic factors found in the egg that direct cells to differentiate into specific cell types. These cytoplasmic proteins and messenger RNA molecules, which are derived solely from the maternal genome, induce an immature cell to follow a particular differentiation route. The other force originates from the external environment of the cell, manipulating the differentiation process towards a specific outcome based on the conditions of its surroundings. This is the result of cell­cell interactions and the release of chemical signals from cells that are detected by neighboring cells, which in both cases trigger signaling pathways within the recipient cells. These signaling pathways cause changes in expression and protein activity that ultimately result in morphogenesis and differentiation. The process of morphogenesis requires the establishment of specific body axes separating regions of the body, an organization related to the symmetry of developing and fully formed . This form of axial orientation guides cells during migration and differentiation, assisting in the correct physical development of body parts. An animal's body can be separated into three major axes. The anterior­posterior axis separates the body into the head region and the tail region. The medial­lateral axis divides the body into central and left/right regions, while the dorso­ventral axis defines the dorsal, or back, region and the ventral, or chest, region. Each of these axes triggers the production of specific proteins needed for the proper development of arms, feet, or the spine. For example, expression of the dorsal gene in the fruit fly generates a protein called Dorsal, which is a factor that guides in immature cells of the embryo (Figure 1). Note that in Figure 1, Dorsal is expressed in a gradient along the dorsal­ventral axis. Expression is highest on the ventral side of the embryo. The differing concentrations of Dorsal impact the expression of specific sets of in those groups of cells. These different patterns of gene expression help to define the dorsal­ventral axis. Mutation of the dorsal gene results in only dorsal tissues being formed; hence the name of the gene.

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Figure 1: Morphogenesis in fruit files. The red fluorescence in this image of a fruit fly embryo (Drosophila) shows the presence of the Dorsal in the immature cells. Dorsal is a that helps define the dorsal­ventral orientation of the embryo. The concentration of Dorsal in each cell will determine which type of cell it will mature into. scale bar = 100 µm © 2011 Nature Publishing Group Chung, K. et al. A microfluidic array for large­scale ordering and orientation of embryos. Nature Methods 8, 171–176 (2011). doi:10.1038/nmeth.1548. Used with permission.

Cytoplasmic factors found in the egg direct cells to differentiate into specific cell types. As the cells in the embryo divide, maternal components of the egg's cytoplasm play a major role in morphogenesis, directing the migration of immature cells and their differentiation into specific cell types. Many of these signaling molecules, which are sometimes called because of their role in directing morphogenesis, form concentration gradients within an embryo. The varying concentration of a morphogen leads to differential gene expression in neighboring groups of cells. Thus, the morphogen gradient functions as positional information that activates developmental processes in cells based on their relative locations. Some morphogens are also secreted from cells, where they serve as chemical signals among neighboring cells. The morphogens initiate a series of cellular responses, such as the induction of neighboring cells to produce a second wave of messengers. These cellular responses again alter gene expression patterns in the affected cells, creating the continuum of reactions necessary for morphogenesis. Test Yourself

If a concentration gradient of a morphogen was not established across an embryo, would morphogenesis as directed by that morphogen still proceed in the same manner? Why or why not?

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Asymmetric cell division facilitates diversity among cells in a developing embryo. The initial division of a zygote generates two identical daughter cells. If maternal cytoplasmic factors are distributed evenly in the cell, then the daughter cells share them equally and at that point share the same fate or potential. But if the morphogens are located primarily in one of the cell http://www.nature.com/principles/ebooks/principles­of­biology­104015/29145882/1 2/8 4/7/2015 Morphogenesis and Differentiation in Animal Development | Principles of Biology from Nature Education poles, then the distribution of these morphogens in the daughter cells will be unequal. This asymmetry sets the stage for two cell lineages in which the progeny of these two daughter cells will be induced to differentiate along separate pathways. Morphogens trigger specific signaling pathways that influence cellular and biochemical reactions, resulting in the maturation of cells and creating fully differentiated cells. This directional signaling can be observed in embryos of the nematode , in which a fluorescent morphogen has been engineered. During interphase, the green fluorescence covers the entire embryo but moves towards one pole at anaphase. After the completion of the initial cell division, the green dye moves exclusively to one daughter cell, establishing polarity across the entire embryo (Figure 2).

Figure 2: Asymmetric cell division in the nematode Caenorhabditis elegans. In embryos of the nematode Caenorhabditis elegans, a morphogen, indicated by the green fluorescence, appears across the entire embryo, eventually moving toward one pole during anaphase. After one cell division cycle, the morphogen has moved to one daughter cell, creating polarity across the embryo. © 2008 Nature Publishing Group Gönczy, P. Mechanisms of asymmetric cell division: flies and worms pave the way. Nature Reviews Molecular Cell Biology 9, 355­366 (2008) doi:10.1038/nrm2388. Used with permission.

Cell­cell interactions and cell signaling are essential for proper patterning of cells, tissues, and organs. How do morphogens establish and maintain a concentration gradient across a developing embryo? Morphogens generally last for a specific duration within the and are eventually removed from circulation. Scientists have tried to induce a gradient in embryos by introducing a dye that does not interact with morphogens. While the dye quickly spreads around the embryos by diffusion, morphogens and other cytoplasmic factors maintain their positions within the developing gradient, in opposition to the embryo's forces of active transport and diffusion. Researchers have proposed three models of morphogen gradient formation (Figure 3). The models also describe how these signaling molecules retain their positions in respective sites within the developing embryo. One model suggests that morphogens move randomly from the extracellular space into cells by Brownian motion. A second model implicates directed cycles of release and uptake of morphogens for transporting and maintaining high concentrations within and around specific cells. A third model suggests that low amounts of cell­surface carbohydrates facilitate uptake of morphogens into cells, while cells with greater amounts of extracellular carbohydrates prevent morphogens from entering cells.

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Figure 3: Proposed models for establishment of morphogen gradients. Three transport theories describe how morphogens enter specific cells, creating gradients that influence : by Brownian motion, through directed cycles of release and uptake, or by the quantity of cell­surface carbohydrate molecules. © 2011 Nature Education All rights reserved. Certainly, morphogens induce cells to differentiate into specific cell types. But do morphogens trigger the production of specific proteins during morphogenesis? Research studies have shown that over the course of morphogenesis, cells secrete such morphogens (Figure 4). For example, in the development of the dorsal in chicks, the morphogen homolog (Shh) influences the production of transcription factors needed for differentiation. Sonic hedgehog also determines which cells undergo cellular activities by activating or suppressing the production of these transcription factors. At approximately 6 hours into morphogenesis, Shh activates production of the transcription factor Olig2 in all cells of the neural tube. Six hours later, Shh facilitates the production of another transcription factor, Nkx2.2, at the periphery of the dorsal neural tube, while the inner regions of the neural tube retain Olig2. At 18 hours, both transcription factors occupy the inner region of the neural tube. By the 24th hour, Shh induces the entire structure to produce Nkx2.2. Throughout this process, Shh also suppresses the production of the Pax7 transcription factor. This regulation of protein production by Shh is an example of how morphogens function during morphogenesis.

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Figure 4: Different morphogens produced during development. During morphogenesis of the neural tube in chicks, the morphogen sonic hedgehog homolog (Shh) influences differentiation by inducing the production of specific transcription factors. Olig2 is stained red and Nkx2.2 is stained green (Pax7 would be stained blue, but is absent from these photos). During the first 6 hours of Shh exposure, the protein Olig2 dominates the entire structure, followed by Nkx2.2 at the 12th hour. At 18 hours, the periphery of the neural tube contains higher concentrations of Nkx2.2, reaching its maximum concentration at 24 hours. Shh prevents the production of the protein Pax7 during the entire process. © 2007 Nature Publishing Group Dessaud, E., et al. Interpretation of the sonic hedgehog morphogen gradient by a temporal adaptation mechanism. Nature 450, 717­720 (2007) doi:10.1038/nature06347. Used with permission. Why is our head on the top of our body and our feet on the floor? Why do a fly's wings appear where they do and not down by its legs? These are questions of patterning along the anterior­posterior access of an animal. A set of genes known as homeotic or Hox genes regulate the anterior­posterior axis of an embryo. Highly conserved groups of Hox genes are found in many animal phyla from fruit flies to humans (Figure 5). Each region of the Drosophila embryo, for example, is dictated by specific Hox genes. One dictates the formation of the mandibular region, while another induces the formation of the labial region. How did scientists study the role of these Hox genes? In mutational studies, researchers removed specific gene segments in the Hox gene cluster to identify morphological defects that would develop in the resulting organism. Comparative analysis also showed that other vertebrate species carry Hox genes, with species­specific modifications to their gene cluster composition and order. DNA analysis allowed for the identification of sequence motifs within Hox genes for binding with other proteins. A counterpart of Hox genes also exists in plants, including some of the MADS­ box and floral patterning genes. http://www.nature.com/principles/ebooks/principles­of­biology­104015/29145882/1 5/8 4/7/2015 Morphogenesis and Differentiation in Animal Development | Principles of Biology from Nature Education

Figure 5: Hox genes and body patterning. Hox gene expression appears in clusters or rows, reflecting the type of development that is observed in the developing embryo. Deletion of specific gene segments in the Hox gene cluster generates morphological defects in most vertebrate species. The colors represent homologous genes between the Drosophila and mouse embryos. © 2011 Nature Education All rights reserved. Another example of body patterning is visible in the spots in the wings of fruit flies. These spots result from the morphogenetic effects of a specific morphogen called Wingless. Secretion of the Wingless morphogen occurs in discrete areas of the wings. Another morphogen, named Yellow, influences spot in the wings of fruit flies as well. Because Yellow appears at sites where the brown pigment melanin later deposits in the adult fruit fly, the Yellow morphogen is believed to provide positional information on patterning. Two other morphogens, Vein spot and Intervein shade, influence the pigmentation patterns along the veins and interveins of the wings (Figure 6).

Figure 6: Morphogens and wing patterns in . Morphogens influence the development of pigmented spots in the wings of fruit flies. In these fluorescence microscopy photos, two morphogens, Vein spot and Intervein, influence pigmentation patterns in the veins (a) and interveins (b) of the wing. (c) Merged fluorescence image with veins stained green and interveins stained red, showing the complementary expression patterns of the two morphogens that give rise to distinct zones in the wing. © 2010 Nature Publishing Group Werner, T., et al. Generation of a novel wing colour pattern by the Wingless morphogen. Nature 464, 1143–1148 (2010) doi:10.1038/nature08896. Used with permission.

http://www.nature.com/principles/ebooks/principles­of­biology­104015/29145882/1 6/8 4/7/2015 Morphogenesis and Differentiation in Animal Development | Principles of Biology from Nature Education molecules are critical for keeping cells connected. The directed movement of tissues in a developing embryo results in the generation of three major germ layers: the ectoderm, endoderm, and mesoderm. These movements range from subtle cell migrations to massive , changing the shape of the entire embryo. How do cells of each remain intact during these movements? Is there a force or mechanism that keeps them together as they slide over other tissues? Critical in this process are a group of cell adhesion molecules called . These are transmembrane glycoproteins that bind cells to one another and to the extracellular matrix. Cytoskeletal structures, such as filaments, within the cell provide support to the cytoplasmic region of the proteins. The sugar­coated extracellular parts of these glycoproteins serve as the recognition sites, often binding to the same molecule on a different cell. This enables cells that express specific cadherin proteins on their surface to stick to each other, while preventing different cell types from binding. At the level, cadherins allow each germ layer to remain connected during embryogenesis.

Spemann's organizer controls the formation of embryonic axes. Even during the early 1900s, biologists speculated about the driving force of morphogenesis. In 1910, Alexander Gurwitsch presented the theory of the , which posited that cells developed into specific body regions in response to specific chemicals secreted by the embryo. By the 1920s, scientists and Hilde Mangold conducted a simple transplantation experiment that confirmed this theory. Their experiment involved embryos of two closely related newt species that followed different patterns of pigmentation. These slight differences allowed a viable embryo to be constructed that also demonstrated which newt was the source of developmental results. The host embryo, Triton cristatus, was entirely non­ pigmented while the donor embryo, Triton taeniatus, showed general pigmentation. Transplantation of a specific portion on the dorsal side of the host gastrula to its donor, thereafter called Spemann's organizer, resulted in the development of a second notochord and neural tube in the host embryo. Interestingly, these secondary structures were non­pigmented, suggesting that these cells originated from the host embryo. Decades later, scientists identified morphogens in these transplanted cells.

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Morphogenesis and Differentiation During Animal Development Summary Test Your Knowledge

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Stem Cells Stem cells are powerful tools in biology and medicine. What can scientists do with these cells and their incredible potential?

PRIMARY LITERATURE

Classic paper: Fruit fly research reveals how complex organisms form (1980) Mutations affecting segment number and polarity in Drosophila. View | Download

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Manipulating Embryos Watch a video explaining Spemann's experiment

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contents Principles of Biology

164 Morphogenesis and Differentiation in Animal Development

Test Your Knowledge

1. What is the series of cellular responses of neighboring cells that creates the continuum of reactions necessary for morphogenesis?

induction morphogen cytoplasmic protein body axes None of the answers are correct.

2. What causes morphogens to generate a gradient?

The morphogens vary in concentration within an embryo. asymmetrical cell division induction elimination All answers are correct.

3. Which of the following suggests morphogens trigger the production of specific proteins?

The morphogen sonic hedgehog influences the production of transcription factors. The morphogen sonic hedgehog determines which cells undergo cellular activity. The morphogen sonic hedgehog influences the activation or repression of multiple transcription factors. The morphogen sonic hedgehog stimulates the production of transcription factors, such as OLIG2, in multiple cells to coordinate protein production in these cells. All answers are correct.

4. Which of the following holds the three germ layers together as they slide over other tissues?

morphogens pheromones

ectoderm cadherins None of the answers are correct.

5. In the Spemann­Mangold experiment, what extra structure(s) developed after the dorsal side of the donor's gastrula was transferred to the host organism?

newt embryos notochord morphogens neural tube a notochord and a neural tube

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IN THIS MODULE

Morphogenesis and Differentiation During Animal Development http://www.nature.com/principles/ebooks/principles­of­biology­104015/29145882/3 1/2 4/7/2015 Morphogenesis and Differentiation in Animal Development | Principles of Biology from Nature Education Summary Test Your Knowledge

WHY DOES THIS TOPIC MATTER?

Cancer: What's Old Is New Again Is cancer ancient, or is it largely a product of modern times? Can cutting­edge research lead to prevention and treatment strategies that could make cancer obsolete?

Stem Cells Stem cells are powerful tools in biology and medicine. What can scientists do with these cells and their incredible potential?

PRIMARY LITERATURE

Classic paper: Fruit fly research reveals how complex organisms form (1980) Mutations affecting segment number and polarity in Drosophila. View | Download

SCIENCE ON THE WEB

Manipulating Embryos Watch a video explaining Spemann's experiment

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162 Embryonic Development Stages of Embryonic Development In animals, embryonic development describes the earliest stages of development. There are stages of embryonic development that are common to all animals, although the specific details do differ. In general, embryos develop through a series of sequential stages involving specific changes in cells and tissues that eventually produce a newborn animal. In the initial stage of development, called fertilization, the gametes (egg and sperm) fuse and create a single cell or zygote. The zygote then undergoes multiple, rapid cell divisions in a process known as . The resulting structure, called a blastula, goes through complex rearrangements, resulting in specialized cell layers. The resulting structure is known as a gastrula. is the process by which these specialized cell layers develop into specific organs. Using classical embryological studies and more recent molecular approaches, scientists have generated a comprehensive picture of how a fertilized egg is transformed into a fully formed organism. Different species exhibit diverse body plans, yet most species share a similar course of embryonic development. For example, a human gene that influences specific cells to develop into a heart has a counterpart in the fruit fly. In flies, this gene, called the tinman gene, is responsible for the development of the dorsal vessel, the insect equivalent of the heart. Because of similarities such as this in the process of animal development, scientists can use a variety of animals as model organisms to investigate how development unfolds. Model organisms are often chosen because they are easily manipulated in the laboratory or possess special features that make them advantageous for studying development. For example, members of the fruit fly genus Drosophila serve as classic model organisms due in part to Drosophila's short life cycle and rapid development, which allow scientists to investigate changes in specific body parts over several generations. In humans, such studies might require decades of observations to generate conclusions. In addition, the of Drosophila are mapped in great detail, and many forms of Drosophila exist that represent specific malformations, conditions, and diseases in other species.

When a sperm fertilizes an egg, a zygote forms. Animal sperm are remarkable haploid gametes. They are designed to swim to an egg, bind the egg, and through a set of chemical interactions with the egg either enter the egg or release their nucleus into the egg so that two haploid gametes can fuse together into a diploid zygote and begin the process of embryonic development. A sperm cell is constructed of three parts: the head, the midpiece, and the tail (Figure 1). The head contains the nucleus and the acrosome. The midpiece is the site of ATP production. Hydrolysis of ATP provides the energy that drives the tail, which is a eukaryotic flagellum.

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Figure 1: Human sperm cells. Sperm are motile haploid gametes. Each sperm cell is made of three parts: a head, which contains the nucleus and the acrosome, the midpiece filled with mitochondria, and the tail, which is a flagellum. © 2011 Nature Publishing Group (left) Lishki, P. V., et al. Progesterone activates the principal Ca2+ channel of human sperm. Nature 471, 387– 391 (2011) doi:10.1038/nature09767. Used with permission. During fertilization, two gametes, an egg and a sperm, fuse, resulting in a zygote (Figure 2). Each of the gametes is haploid and thus contributes half of the genes that the embryo will possess. Fusion of the two gametes creates a diploid zygote with a complete genome. This is the main purpose of fertilization: to form a diploid cell that can then become an entire organism. But the process of animal development also requires that the egg become activated. This process is also initiated by the fusion of sperm and egg. As we'll see, activation of the egg involves fairly rapid changes within the egg that trigger the beginning stages of embryonic development. When a sperm comes into contact with the surface of an egg (Figure 2), chemical signals cause the release of enzymes from the head of the sperm that dissolve part of the egg's protective external layer, exposing the egg's plasma membrane. This enables the sperm and egg plasma membranes to come into close proximity, and, in particular, it allows surface proteins on the sperm to bind to specific receptors on the egg. The ­protein binding stimulates a set of changes that cause the sperm and egg plasma membranes to fuse. In addition, the surface of the egg undergoes changes that prevent other sperm from reaching the plasma membrane. Let's now look at these steps in more detail.

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Figure 2: Fertilization of an egg. The surface of the egg plays an important role in the process of fertilization. When a sperm comes in contact with the egg's surface, part of the egg's protective external layer dissolves, exposing its plasma membrane and allowing the fusion of the two gametes. Don W. Fawcett/Science Source

Much of our knowledge about the changes in the surface of animal eggs at fertilization comes from investigations of sea urchins, marine animals from the phylum Echinodermata. How can such a simple animal be useful for developmental studies of far more complex animals? Sea urchins serve as essential model organisms for this research mainly due to the large number of easily collected gametes produced. The external fertilization of eggs, occurring outside the sea urchin's body, allows researchers to readily observe development in the laboratory. Sea urchins also follow a developmental process similar to vertebrate species. Upon their release into seawater, sea urchin eggs produce molecules on their jelly coats that attract sperm. Once the head of a sperm comes in contact with an egg's jelly coat, proteins in the jelly trigger an acrosomal reaction. This response starts with the release of hydrolytic enzymes from the apex of the sperm's head, or acrosome. The hydrolytic enzymes destroy a portion of the egg's jelly coat, which allows a filamentous structure, called the acrosomal process, to extend from the sperm's head, elongate, and diffuse through the jelly coat. The acrosomal process contains the proteins that attach to specific receptors on the plasma membrane of the egg. The binding between acrosomal proteins and egg receptors is species specific (it is often referred to as a "lock­and­key" type of binding), which ensures that only gametes of the same species can fuse. A similar fertilization process occurs in mammals (Figure 3). When a sperm approaches the surface of a mammalian egg, it first encounters the zona pellucida, a layer of extracellular matrix that surrounds the egg. Proteins on the head of the sperm bind to ZP3, which is both a component of the zona pellucida and the egg's receptor for the sperm. This binding activates the acrosomal reaction, releasing enzymes that break down the zona pellucida. This enables the sperm to reach the egg's plasma membrane, where the two membranes fuse together. Binding of the two plasma membranes first initiates a depolarization of the membrane, which is a fast block to polyspermy, as it is in sea urchin eggs. This is followed by a cortical reaction that serves as a slow block to polyspermy. Test Yourself http://www.nature.com/principles/ebooks/principles­of­biology­104015/29145869/1 3/9 4/7/2015 Embryonic Development | Principles of Biology from Nature Education Test Yourself

How would fertilization be affected if an acrosome did not contain hydrolytic proteins?

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What mechanism ensures that only one sperm will fertilize an egg when many sperm cells are swimming toward the egg? That is, what prevents polyspermy — the fertilization of an egg by two or more sperm? Once the acrosomal proteins and egg receptors join, the plasma membranes of the sperm and the egg fuse. This allows the entry of the sperm nucleus into the egg cytoplasm. Membrane fusion also opens ion channels present on the plasma membrane of the egg, allowing sodium ions to move into the egg. The presence of these ions decreases the membrane potential of the plasma membrane; that is, it depolarizes the membrane. Depolarization happens very quickly, taking only a few seconds. The change in the charge of the plasma membrane prevents other sperm cells from binding to the egg, acting as a fast block to polyspermy. Depolarization provides a very brief block to polyspermy. Vesicles located just underneath the egg's plasma membrane, in a region of the cytoplasm called the cortex, further extend this blocking effect. Once gametes fuse, these enzyme­containing vesicles quickly merge with the egg's plasma membrane. Enzymes from cortical vesicles enter the perivitelline space, which is the region between the egg's plasma membrane and its extracellular sheath, called the vitelline layer. The vitelline layer then separates from the egg and hardens into a fertilization envelope. The change in egg structure due to the action of vesicle enzymes is called the cortical reaction or the slow block to polyspermy. Other enzymes dismantle sperm­binding receptors on the egg's plasma membrane, especially those close to the area where the sperm attached to the egg. All these events help block polyspermy (Figure 3).

Figure 3: Fusion of mammalian sperm and egg and the subsequent cortical reaction. http://www.nature.com/principles/ebooks/principles­of­biology­104015/29145869/1 4/9 4/7/2015 Embryonic Development | Principles of Biology from Nature Education (a) A sperm approaches the surface of a mammalian egg. (b) The sperm first encounters the zona pellucida, a layer of extracellular matrix that surrounds the egg. (c) Proteins on the head of the sperm bind to ZP3, its receptor on the egg. This activates the acrosomal reaction, releasing enzymes that break down the zona pellucida and enable the sperm to reach the egg's plasma membrane. (d) Binding of the two plasma membranes first initiates a fast block to polyspermy followed by a cortical reaction that serves as a slow block to polyspermy. © 2014 Nature Education All rights reserved.

After fertilization, cleavage occurs. After fertilization, the zygote divides repeatedly during a stage known as cleavage. This division consists largely of the DNA synthesis and mitosis phases of the cell cycle, bypassing the protein synthesis and growth stages. Because there is no , cleavage results in the formation of small cells called blastomeres. Cleavage begins with the relatively large single­celled zygote. Since there is little protein synthesis during cleavage, the cytoplasm of the zygote becomes portioned into the blastomeres. This results in blastomeres that may contain distinct cytoplasmic proteins and mRNA. Cleavage, thus, is the first step in creating asymmetry, which is essential for embryonic development. Test Yourself

Why is the total number of blastomeres at any stage of cleavage theoretically always even­ numbered?

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The zygotes of most animal species, including those of frogs and humans, possess a yolk. This organic material supplies nutrients to the embryo during development. The yolk is concentrated at one region of the zygote, called the vegetal pole. The region of the zygote opposite the vegetal pole is called the animal pole. During cell division, a groove known as a cleavage furrow develops as a single cell separates into two. The first two cleavage furrows of frog embryos develop parallel to the meridian, forming a line between the vegetal and the animal poles. The third cell division occurs perpendicular to the first two divisions. The yolk impedes the process of cell division, so in the eight­cell frog embryo the cells at the vegetal pole are larger than the four at the animal pole because the yolk pushes the cleavage furrow closer to the animal pole. This asymmetrical cleavage pattern continues during subsequent cell divisions, so that the cells closer to the animal pole are smaller than the cells near the vegetal pole (Figure 4). After several more rounds of cell division, the cells produced by cleavage form a sphere, called the blastula, that contains a fluid­filled cavity called the blastocoel. Depending on the type of animal, the blastula can be made of from 128 cells to thousands of cells. Formation of the blastula marks the end of cleavage. Experimental studies on blastomeres make use of dyes that label specific cells of a blastula. As the blastula undergoes the next stages of development, the labeled cells rearrange, migrating to their destination within the differentiating embryo. This experimental technique, called fate mapping, allows scientists to track various processes that each blastomere undergoes during embryonic development.

Figure 4: Cleavage and the development of the blastocoel. The early stages of embryonic development feature multiple divisions.

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During , three germ layers form in an embryo. In the next stage of embryonic development, the blastula undergoes substantial cellular rearrangements that result in the formation of the germ layers that will eventually develop into tissues and organs. The organization of these germ layers influences cell and tissue arrangements that give shape to an animal's body. This process of cell movements and reorganization is called gastrulation. The embryo composed of these layers of cells is called a gastrula. Each germ layer in the gastrula will give rise to specific types of cells. Animals in which the gastrula is a two­layered structure are called diploblasts, while animals that generate three germ layers are referred to as triploblasts. Diploblasts consist of the outer ectoderm and the inner endoderm. Triploblasts possess both ectoderm and endoderm layers, and a third middle layer called mesoderm. Simple animals, including many radially symmetrical species, are diploblasts. What role do these germ layers perform in the developing embryo? One might assume that the ectoderm forms the exterior of animal, the mesoderm forms the internal organs, and the endoderm forms the digestive cavity. However, the actual fate of each germ layer is more complex. Some organs originate from specific germ layers, while others develop from combinations of germ layers. For example, most endocrine glands of mammals arise from the endodermal layer, while the adrenal glands develop from both the ectodermal and mesodermal germ layers. In sea urchins, gastrulation begins when some cells separate from the vegetal pole of the blastula and disperse throughout the blastocoel as mesenchyme cells. Other cells at the vegetal pole elongate in shape, causing that end of the embryo to dip inward in a process called . The shape of the entire embryo changes as a result of the movement and modification of these cells. With further modification of nearby cells, the invagination develops into a deeper indentation called the archenteron. The initial opening formed by the archenteron, known as the blastopore, later develops into the anus of the animal. The archenteron http://www.nature.com/principles/ebooks/principles­of­biology­104015/29145869/1 6/9 4/7/2015 Embryonic Development | Principles of Biology from Nature Education reaches and fuses with the inner lining of the blastocoel. This region eventually develops into the mouth. As gastrulation nears completion, the surface cells of the embryo form the ectoderm. The cells on the surface of the archenteron develop into the endoderm, while the cells between these layers become the mesoderm (Figure 5). The steps described in the previous paragraph are for animals called deuterostomes, which means "second mouth." Gastrulation follows similar steps in amphibians and mammals, with modifications allowing for the more intricate arrangements of blastomeres in these embryos (Figure 5). Amphibians and mammals are two more examples of deuterostomes. There is an alternative gastrulation pattern in which the blastopore becomes the mouth and the second opening of the archenteron becomes the anus. Animals that develop in this fashion are called protostomes ("first mouth") and include arthropods, nematodes, , and molluscs.

Figure 5: Gastrulation. http://www.nature.com/principles/ebooks/principles­of­biology­104015/29145869/1 7/9 4/7/2015 Embryonic Development | Principles of Biology from Nature Education Gastrulation is a stage of embryonic development featuring marked differentiation of cells. Gastrulas from a sea urchin, frog, and human are shown. Note the similarities and differences between them. © 2014 Nature Education All rights reserved.

Following gastrulation the central nervous system begins to form. In organogenesis, cells and tissues of the developing embryo start to form into organs. The central nervous system develops in vertebrate species through the process of . Neurulation starts with mesodermal cells forming a notochord, a column of cells positioned along the dorsal region of the embryo. These cells produce signaling molecules that trigger the ectodermal cells above to differentiate into elongated cells that are collectively known as the . The neural plate folds inward until its edges, called neural folds, pinch inward toward each other. The fusing of the neural folds creates a hollow neural tube that extends from the anterior to the posterior regions of the developing embryo (Figure 6). The neural tube serves as the forerunner of the brain and the spinal cord. In vertebrate species, two groups of cells involved in neurulation go on to develop into other tissues and organs. The neural folds detach from the overlying ectoderm as the neural tube is formed. One group of cells, the neural crest cells, emigrates from the dorsal neural tube as mesenchymal cells. These cells continue to migrate to various regions of the embryo and ultimately form teeth, parts of the skull, and components of the peripheral nervous system, among other parts of the animal. Sequential blocks of mesodermal cells, called somites, form along the notochord. Somites develop into a variety of tissues, including muscle and bone. Vertebrae, for example, develop from somites.

Figure 6: Neural tube formation. Neurulation starts with infolding of the neural plate. The neural folds fuse, forming a neural tube. http://www.nature.com/principles/ebooks/principles­of­biology­104015/29145869/1 8/9 4/7/2015 Embryonic Development | Principles of Biology from Nature Education © 2014 Nature Education All rights reserved.

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How does the sequential arrangement of blocks of somites in the developing embryo aid in the development of adult vertebrates?

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Organ formation occurs once the central nervous system is in place. Organogenesis, or the formation of organs, follows a similar pattern in most vertebrates. The first organs developed are those of the central nervous system, including the brain, the spinal cord, and other related neural structures such as the eyes, nerves, and ganglia. Soon after the central nervous system emerges, other organs develop. The heart forms right after the development of the brain. The embryonic heart mainly consists of muscle tissues that pump blood for circulation across the animal's body. The organs of the respiratory system, namely the , bronchus, and bronchioles, develop next. The initial structures are not capable of functioning independently as respiratory organs, but through continued cell and tissue differentiation, the lungs will be able to function once they are needed for the animal's survival. The digestive system, consisting of the stomach, intestines, and anus, also develops during organogenesis. These organs also acquire the capacity to function during later stages of development. What factors stimulate the germ layers to undergo organogenesis? Morphogens are molecules that convey messages regarding a tissue's position within the developing embryo and information about its neighboring tissues. These morphogens are critical signaling molecules that assist in organogenesis. Through this cellular mechanism of signaling, each cell is apprised of which activities should or should not be performed. The end result of organogenesis is an animal with a complete set of organs, each of which consists of differentiated cells.

IN THIS MODULE

Stages of Embryonic Development Summary Test Your Knowledge

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Stem Cells Stem cells are powerful tools in biology and medicine. What can scientists do with these cells and their incredible potential?

Cancer: What's Old Is New Again Is cancer ancient, or is it largely a product of modern times? Can cutting­edge research lead to prevention and treatment strategies that could make cancer obsolete?

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contents Principles of Biology

162 Embryonic Development

Test Your Knowledge

1. What organ system develops first during organogenesis?

cardiovascular system respiratory system nervous system digestive system All of the organ systems develop simultaneously.

2. A developing organism forms a neural plate. What is the next step in neural plate development?

It forms the vertebrae. It becomes a somite. It will fold into a tube. It becomes the brain. It turns into the blastopore.

3. What does the very tip of the sperm head contain that helps it penetrate the egg?

gamete lipids jelly coat hydrolytic enzymes chromosomes

4. Which of the following events occurs in a stage prior to gastrulation?

germ cell layers form the gastrula takes shape the cortical reaction takes place the ectoderm develops the endoderm develops

5. Neural crest cells emigrate from the dorsal neural tube as ___ cells, which eventually form the teeth and skull. The ___, or mesodermal cells, develop into tissues such as muscle and bone tissues.

ectodermal, somites endodermal, ectoderms mesenchymal, ectoderms mesenchymal, somites mesenchymal, endoderms

6. Which of the following actions might indicate that a fertilized egg failed to develop normally after several days?

The egg cell had increased in size. The egg divided into several small cells. A hole formed in the center of the new cells. A deep indentation formed in the cell. All answers are correct. http://www.nature.com/principles/ebooks/principles­of­biology­104015/29145869/3 1/2 4/7/2015 Embryonic Development | Principles of Biology from Nature Education

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IN THIS MODULE

Stages of Embryonic Development Summary Test Your Knowledge

WHY DOES THIS TOPIC MATTER?

Stem Cells Stem cells are powerful tools in biology and medicine. What can scientists do with these cells and their incredible potential?

Cancer: What's Old Is New Again Is cancer ancient, or is it largely a product of modern times? Can cutting­edge research lead to prevention and treatment strategies that could make cancer obsolete?

SCIENCE ON THE WEB

Fast Forward on Brain Development Fast forward on brain development

page 833 of 989

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