Molecular Biology of the Cell - Volume 3 - Alberts B., Bray D., Lewis J., Raff M., Roberts K., Watson J. 1994

From Cells to Multicellular Organisms
Cellular Mechanisms of Development
Organogenesis: The Coordinated Assembly of Complex Tissues

Up to this point, we have considered the establishment of spatial Organization primarily in terms of changes in Cell properties while paying relatively little attention to cell position; we traced the accumulation of these changes within individual Tissues, specifically examining the epidermis in *Drosophila* and the skeletal Connective Tissue in vertebrate limbs. In reality, however, due to complex morphogenetic movements during Embryogenesis, all Organs are intricate composites of diverse tissues made up of Cells of different origins that follow distinct rules. Cell movements bring all these components together. In this final section, we will examine how positional information directs cell movements and coordinates the construction of complex organs such as limbs.

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Fig. 16-77. Cells from various Regions of the early amphibian embryo sort themselves out according to their origin. In this classic experiment, shown schematically here, the mesoderm, neural plate, and epidermal cells were dissociated. Upon reaggregation, the cells formed a Structure resembling a normal embryo, with a neural tube on the inside, epidermis on the outside, and mesoderm in between. (P. L. Townes, J. Holtfreter, J. Exp. Zool., 128, 53-120, 1955; modified.)

16.6.1. Selective adhesion stabilizes tissue structures formed by differently determined cells [65, 66]

During animal development, cells move, proliferate, and come into contact with one another, resulting in the intermingling of cell lineages. In chimeric mouse embryos, for instance, cells from two original morulae become mixed, so that the adult Organism contains a haphazard mixture of cells of two genotypes (see Section 16.2.5). However, if cell displacement occurs after determination, it can lead to disruptions in the spatial distribution of cells with different differentiation states. The acquisition of properties dictated by cell position prevents random cell mixing. The compartment phenomenon in *Drosophila* (see Fig. 16.5.15) illustrates one way this is achieved. Presumably, determined cells remain within their respective compartments through selective adhesion to Cells of the same determination state. Cells expressing identical molecular "addresses" likely adhere to one another more strongly than to cells with different molecular addresses. Apparently, the positional information encoded by the activation of genes such as *engrailed* and *Urabithorax* is manifested through the selective deployment of cell-surface adhesion molecules.

In early amphibian embryos, the stabilizing effects of intercellular adhesion on tissue organization—ensuring the proper spatial arrangement of different cell types—are likely strong enough to restore normal architecture even after artificial cell dissociation yields a shapeless, disordered mass. Mesodermal, neural plate, and epidermal cells can sort themselves out from such a mixture to form structured configurations with the epidermis on the outside, the mesoderm beneath it, and a neural tube-like structure on the inside (Fig. 16-77). Studies on chick and mouse embryos suggest that this behavior is determined, at least in part, by a family of Ca²⁺-dependent cell-adhesion Glycoproteins known as cadherins (see Section 14.3.7). These and other Ca²⁺-dependent cell-adhesion molecules, such as N-CAM (see Section 14.3.6), are differentially expressed in various Tissues of the early embryo, and Antibodies against these molecules disrupt normal selective adhesion among cells of the same type.

16.6.2. Spatial patterns formed by cell-adhesion molecules regulate the character of morphogenetic movements [66, 67]

Changes in the expression patterns of various cadherins correlate closely with shifts in cell association during Gastrulation, neurulation, and somite formation (Fig. 16-78); such changes in early embryogenesis can be regulated by—and at least partially depend upon—cadherin distribution. In particular, cadherins likely play a crucial role in controlling the formation and dissolution of epithelial layers and cell clusters. Consequently, the movements involved in building the early embryo are governed by chemical differences among cells located in different positions.

This general principle is illustrated by numerous other Examples. During The formation of the adult wing, the *Drosophila* imaginal disc epithelium must flatten, elongate, and fold in a specific manner. Although this process remains largely enigmatic, it is presumably driven by the localized expression of specific cell-surface adhesion molecules, which are now being identified using Monoclonal Antibodies. The distribution of such position-specific cell-surface molecules correlates closely with the folding pattern of the disc during metamorphosis (Fig. 16-79); some of these molecules have been shown to belong to a family of cell-surface receptors called Integrins (Section 14.2.17). Unlike cadherins, integrins mediate cell attachment to Extracellular matrix components. As noted previously, such cell-matrix interactions play a vital role in gastrulation (see Section 16.1.5). Intercellular adhesion molecules, as well as cell-surface and matrix adhesion molecules, can be viewed as Two Types of key machinery for translating positional information into the Spatial Organization of morphogenetic movements.

16.6.3. In vertebrates, the mesoderm is the primary bearer of positional information [68]

It is quite evident that the positional information possessed by cells can manifest in various ways. This is especially well illustrated by The Development of complex organs. A vertebrate limb is formed by six different tissue types that make up connective tissue (bone, tendons, etc.), epidermis, Muscle, Blood vessel linings, nerve cell axons and their glial sheaths, pigment cells, and the hematopoietic tissue of the Bone Marrow. Although all these components possess their own well-defined structure, they make distinct contributions to the limb as a whole. In flies, which are small, the surface-to-volume ratio is very high, and the ectoderm-derived epidermis plays a dominant role both in forming the mechanical exoskeleton and in coordinating spatial pattern formation. In vertebrates, which are substantially larger than insects, the roles of the germ layers are modified. The structural framework of the body is formed by Connective Tissues (derived primarily from the mesoderm); as we shall see, these tissues also play a coordinating role in spatial organization during organogenesis. Indeed, experiments on amphibians early this century demonstrated that the mesoderm plays a critical role in establishing spatial organization at the very earliest stages of body plan formation.

Fig. 16-79. A *Drosophila* imaginal disc treated with monoclonal antibodies recognizing the position-specific antigen PS2. The sharp boundary of the stained region corresponds to the future wing margin, where the dorsal and ventral wing epithelia meet to form a fold. The dashed line marks the compartment boundary along the anteroposterior axis. (V. C. Wilcox, D. L. Bower, R. J. Smith, Cell, 25, 159-164, 1981.)

Fig. 16-78. Changes in the expression patterns of three cadherins at several successive stages of early chick or mouse embryo development, shown in transverse sections through the developing neural tube and somites. Spatially restricted cadherins may help regulate the morphogenetic movements involved in forming the neural tube, notochord, somites, neural crest, and sclerotomes. (M. Takeichi, Trends in Genetics, 8, 213-217, 1987.)

As already mentioned (see Sections 16.1.7–16.1.9), the vertebrate Nervous system develops from the ectoderm under the inductive Influence of the underlying mesoderm. If a piece of mesoderm lying directly beneath the prospective neural tube region of one gastrulating amphibian embryo is transplanted under the ectoderm on the ventral side of another embryo, the overlying ectoderm will thicken and fold, forming a segment of neural tube at this ectopic site. The Specific characteristics of this segment will depend on the Water/144.html">Origin of the mesoderm. If the mesoderm was taken from an anterior region, Forebrain structures will form from the ectoderm; mesoderm from a posterior region will induce the formation of a Spinal Cord segment. This suggests that ectodermal cells acquire specific positional values depending on the positional values of the underlying mesodermal cells.

The regulation of spatial organization by underlying connective tissue is observed during the development of many vertebrate organs. For example, the Skin and gut, along with all their glands, appendages, and local specializations, acquire their characteristic architectures through specific interactions in which connective tissue components provide the apposed epithelium with appropriate positional information. Skin covering the limbs serves as an excellent model for studying these phenomena.

16.6.4. The pattern and distribution of epidermal derivatives are controlled by the dermis [66, 69]

Skin consists of two layers: the epidermis (an ectoderm-derived epithelium) and the dermis (a connective tissue composed of fibroblasts largely of mesodermal origin). The epidermis gives rise to keratinized Skin Appendages (Hair, feathers, scales, and claws) as well as numerous glands. Different body regions feature distinct types of keratinized derivatives: the back, wings, and upper legs of a chicken, for instance, bear rows of feathers (Fig. 16-80), whereas the lower legs bear rows of scales. Furthermore, depending on their position within each row, feathers and scales can vary in shape and color. If the epidermis from the leg of a chick embryo—where it normally forms scales—is combined with back dermis—where it normally forms feathers—it will subsequently develop feathers instead of scales (Fig. 16-81); the reciprocal combination yields the opposite result. In general, the dermis controls not only the type of epidermal derivative but also its precise Location. Here we encounter another manifestation of non-equivalence (see Section 16.4.6): the dermis from different body regions appears morphologically identical yet differs in its ability to induce specific differentiation in the overlying epithelium.

Fig. 16-80. Arrangement of feather germs on the back of a 9-day-incubated chick embryo. Note that the primordia in each row are evenly spaced. (Courtesy of A. Mauger and P. Sengel.)

The molecular mechanisms by which connective tissue controls epithelial differentiation remain unclear, but some success has been achieved in identifying the molecules that govern the morphogenetic movements of cells giving rise to hairs, feathers, or glands. Here too, intercellular adhesion types play a critical role, as does cell-matrix adhesion. Within the connective tissue component, mechanical forces exerted on Collagen secreted by fibroblasts lead to the aggregation of these cells at sites of appendage formation. Simultaneously, changes in the expression patterns of cell-adhesion molecules such as N-CAM and E-cadherin are observed in both the connective tissue and the overlying epithelium, likely regulating cell shape and mutual packing (see Sections 14.3.6 and 14.3.7). At the epithelial-mesenchymal interface, various basement membrane components (see Section 14.2.15)—including Laminin, Proteoglycans, and collagen—are synthesized and degraded, with both Synthesis and Breakdown being tightly controlled to facilitate epithelial outgrowth and folding.

Fig. 16-81. Scheme of experiments demonstrating that the type of skin derivative is determined by the dermis.

16.6.5. Many types of migrating cells colonize the vertebrate limb connective tissue [11, 70]

Connective tissue permeates the entire vertebrate body. In the limbs, connective tissue forms bones and Cartilage, tendons and ligaments, skin, muscle sheaths, the outer layers of blood vessel walls, nerve sheaths, and the interstitial tissue that binds all these components together. These forms of connective tissue are composed of fibroblasts and closely related cells embedded in an extracellular matrix enriched with collagen that they secrete. All of these diverse cells develop from mesenchyme, an uncommitted embryonic tissue filling the limb bud; its origin can be traced back to the lateral plate mesoderm adjacent to the somites of early embryos (see Fig. 16-15). With the exception of the overlying epidermis, all Other components of the limb derive from a population of migrating cells that originate outside the lateral plate. Before reaching their destination and contributing to The structure of the adult animal, these cells must undertake a long journey through the embryonic connective tissue.

Such migration was demonstrated in experiments involving the transplantation of embryonic quail cells into chicken embryos. Although the quail closely resembles the chicken, its cells are easily distinguished in histological preparations because they contain a large, densely staining block of heterochromatin associated with the nucleolus. This nucleolar marker makes it easy to identify the transplanted cells regardless of where they end up within the embryo. If the tissue of a specific group of somites in a chicken embryo is replaced with equivalent tissue from a quail prior to wing bud formation, all the muscle cells of the wings (and only them) will originate from the quail (Fig. 16-82). Evidently, future muscle cells migrate into the limb bud region and remain there, outwardly indistinguishable from other cells but already determined, until the time of their differentiation comes.

Another important example of migrating cells is provided by cells originating from the neural crest, a region located near the neural tube (Fig. 16-83) (see Section 16.11.9). The migratory capacity of these cells was demonstrated in a similar manner by replacing the neural crest in a chick with that of a quail, with the quail neural crest cells being identified by the nucleolar marker. Like glial cells, which form the myelin sheaths of nerve cell axons, pigment cells of the limb derive from neural crest cells. Sensory and autonomic axons of the limbs are outgrowths of Neurons that arose from neural crest cells. (Voluntary motor axons, by contrast, are outgrowths of spinal cord motor neurons).

16.6.6. The Spatial Organization of Limb Connective Tissue Is Independent of the Cells Populating It [71]

If the tissue of the somites, neural crest, and/or neural tube is destroyed in an early embryo before the onset of limb bud formation, limbs lacking specific classes of migrating cells or nerve fibers can readily be obtained. In general, such limbs are quite normal in many respects. For example, one can obtain limbs devoid of muscle cells, yet they possess a normal Skeleton, skin, and sensory nerves; even tendons develop normally, although they subsequently degenerate gradually in the absence of the Muscles that pull on them. Similarly, a limb devoid of nerves and all neural crest derivatives develops a normal skeleton, skin, and muscles, but the muscles, lacking neural stimulation, subsequently degenerate gradually. The internal structures of the limb will not develop normally in the absence of the entire epidermal covering, but partial removal of fairly substantial areas of the epidermis does not disrupt normal development.

Fig. 16-82. If the somite cells of a chicken embryo are replaced with equivalent quail somite cells after two days of incubation, and histological preparations of the wing region are made a week later, it turns out that the wing muscle cells formed from the transplanted quail somites.

Fig. 16-83. Main migration pathways of neural crest cells in a chicken embryo (schematic transverse section of the mid-body). Cells migrating directly beneath the ectoderm (superficial pathway) give rise to pigment cells of the skin; cells moving along the deep pathway through the somites give rise to sensory and sympathetic ganglia, and in part to the Adrenal Glands (see also Fig. 14-55).

Thus, the spatial organization of connective tissue is virtually independent of other limb components. Moreover, these other limb components possess their own spatial organization, the establishment of which is largely determined by the connective tissue. We have already discussed how this occurs using the epidermis as an example (see Fig. 16-81); using analogous tissue transplantation experiments, it can be demonstrated that the same holds true for migrating cell populations such as muscle cells, nerve cell axons, and pigment cells. Cells of all these types generally form structures that conform to the host limb, regardless of which region of the embryo they originate from. If connective tissue as such acts as a kind of central source and repository of positional information for the vertebrate limb, how does it exert its organizing influence on migrating cells?

16.6.7. Connective Tissue Determines the Migration Pathways and Final Destination of Migrating Cells [11, 72]

In principle, There are five main ways by which connective tissue controls the populations of cells populating it. It can determine:

1) the pathways along which cells move;

2) the sites where migrating cells arrive;

3) the extent of proliferation;

4) the mode of differentiation;

5) the probability of survival.

The Importance of each of these control mechanisms varies depending on the type of migrating cell, but none of them has been studied in sufficient detail. In fact, virtually nothing is known about the Molecular Basis of the connective tissue positional value system upon which its spatial organization is founded. Currently, monoclonal antibodies are just beginning to be employed to reveal position-dependent differences in the distribution of cell surface molecules.

However, certain General Principles of cell migration are beginning to come to light. The behavior of all migrating cells is governed by the MECHANISMS OF CELL adhesion and recognition discussed in Chapter 14; these mechanisms serve as fundamental prerequisites for normal organogenesis. In particular, migrating cells must establish close contact with the extracellular matrix or The surface of other cells. Fibronectin is likely the most crucial (though not the only) substrate component for many migrating cells; antibodies and Peptides that block cell surface fibronectin receptors are capable of disrupting neural crest cell migration in numerous regions of the embryo, as, for example, blocking cell migration during gastrulation (see Section 16.1.5). The universality of certain mechanisms involved in guiding migrating cells to their destinations becomes clearer from studies of mutant mice carrying Steel or dominant-spotting Mutations. In such mutants, pigment, hematopoietic, and primordial Germ Cells fail to reach their destinations in the skin, bone marrow, and Gonads, respectively. The dominant-spotting mutation results in a defect intrinsic to the migrating cells themselves, whereas Steel mutants possess defects in the connective tissue where the migrating cells take up residence.

We are only beginning to comprehend the mechanisms by which limb connective tissue regulates cell migration along specific pathways or, in other words, directs them to specific addresses, but it can be stated with certainty that this guidance is determined by positional information inherent in the connective tissue cells. For instance, the surface of cells with different positional values may possess different properties or secrete different extracellular matrix components. As a cell moves through connective tissue, it continuously extends protrusions, using them to sample the immediate environment and evaluate subtle signals to which these cells are uniquely sensitive through the specific Selection of surface receptor Proteins. Within The Cell, these receptor proteins are linked to the Cytoskeleton, which drives its movement. Protrusions formed at different regions of the cell surface are, as it were, in a constant state of "tug-of-war," resulting in cell translocation toward the direction of strongest substrate adhesion (see Section 11.6.4) until the cell reaches a region where adhesive forces are balanced or so strong that the cell cannot detach from the surface. Chemotaxis plays an important role in this movement, as does the interaction among migrating cells (see Section 14.3); these processes can lead either to the arrest and aggregation of cells in a single area or to their widespread dispersion through mutual repulsion.

16.6.8. The Study of Nervous System Development Poses A number of Special Problems [73]

Our Discussion of cell migration has led us to a topic that has not yet been considered in general: the development of The Nervous System. This process appears to be one of the most enigmatic. The fundamental questions of developmental biology examined in this chapter can be summarized as follows: how different cell types arise in the organism, and how these cells reach their appropriate locations. The nervous system presents an additional problem: how correct connections are formed between cells. Most other cell types can be regarded as point-like objects, each occupying a specific position and possessing specific intrinsic properties. A neuron, however, is not inherently a point-like object: it is enormously extended by a long axon and dendrites that connect it to other cells. If these connections are erroneous, the functioning of the nervous system will be impaired. The processes by which various neuronal types arise and their cell bodies are packed into a regular structure can be explained based on the same principles as for other cells. But the ordered growth of axons and dendrites and the formation of a correct synaptic system represent phenomena of a different order. The leading tip of a growing axon or dendrite crawls in much the same way as a migrating cell: it can be called the migrating organ of a stationary cell. The factors controlling its movement are in some ways the same as those controlling cell movement; these are specific types of adhesion, and so forth. However, as we study how axons relate to other cells, interact with other nerve endings, and acquire The ability to form synapses, new problems arise that require a different approach. Therefore, we defer our Overview of nervous system organization (the driving force of development) to Chapter 19.

Conclusion

The positional values acquired by cells during the spatial ORGANIZATION OF THE embryo are expressed through the adhesive properties of their surface as well as their internal biochemistry. Cells of the same type tend to interact with one another and segregate from different, distinct cells; in this way, spatial organization is stabilized, and cells retain the capacity for spontaneous sorting when artificially mixed. Changes in the pattern of adhesive properties underlie morphogenetic processes such as gastrulation, neurulation, and somite formation. Because the positional value characteristics of a given cell class are manifested through alterations in cell Surface Properties, they can guide the migration of other embryonic cell populations during the assembly of complex tissues or organs. In vertebrates, connective tissue cells are likely the primary bearers of positional information. Dermal connective tissue cells of the skin are capable of controlling the regional specialization of the epidermis, which forms feathers and scales. Similarly, limb connective tissue cells control and coordinate the formation of structures built by migrating cell populations, which include muscle cells (somite derivatives), nerve cell axons (from the Central Nervous System and peripheral ganglia), and pigment cells (neural crest derivatives). Although many general-purpose Cell Adhesion molecules have now been identified, and some have been shown to play central roles in these processes, the molecular mechanisms directing cell migration along specific routes to precise destinations within the limbs remain unknown.

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