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Epithelial-mesenchymal transformation (EMT) creates a family of invasive cell types from the relatively sedentary epithelial cells that line the surfaces of the body. The mesenchymal cell’s primary trait is that, unlike the epithelium of origin, it can invade extracellular matrix and migrate great distances in the embryo. It is a bipolar cell with a very active front end rich in filopodia that apparently drive motility by providing new actin cortex for the myosin endoplasm of the fibroblast to slide forward on. In this chapter, we describe the progression of EMTs as they actually occur in the vertebrate embryo from primitive streak stages to craniofacial remodeling stages in older embryos. We propose a mechanism of TGFβ driven LEF-1 transcription that may be responsible for most, if not all, embryonic EMTs that result in formation of fully active, invasive mesenchymal cells, and we emphasize the importance of studying physiologically relevant signal transduction pathways that lead to the acquisition of invasive motility in vivo, rather than pathways that give rise to nonmotile, stress-fiber rich cells in vitro.

Developmental biology constitutes a unique field to study cell dynamics within an organism. Transitions from epithelial to mesenchymal architectures represent major morphogenetic events during development. In this chapter, trophectoderm and mesoderm formation in the mouse is analyzed in detail to exemplify general features of epithelial to mesenchyme transition at the level of the organism, tissues, cells and molecules. As a conclusion, importance of regulation of these processes in embryos and adults is stressed, dysregulations leading to cancer formation and progression.

The concept of the epithelial-mesenchymal transition (EMT) arose from developmental biology, (see ref. 1) where EMT occurs in many situations, each being predictable, stereotyped and with the outcomes often dramatic. The EMT of the neural crest (NC) is an example of this event in development. In its own right; the NC has been ranked as a “fourth germ layer” by Hall.[] The tissues and structures to which the NC gives rise is widespread in the body and diverse in cell types, ranging from craniofacial connective tissues to peripheral nerve and glial cells to skin pigment cells.[] In addition, abnormalities involving NC development seem to be disproportionately represented in human birth defects. The NC is important for evolutionary research too, because it is the only organ system unique to vertebrates. Its appearance in evolution is suggested to have enabled the massive adaptive radiation of these chordates. Technically, the experimental approaches for developmental biology, described as “cutting, labeling and pasting”,[] have shown the NC to be a particularly accessible, manipulatable and robust subject, with relatively straight-forward evaluation of the results in terms of altered developmental patterns. Thus because of its importance and technical advantages, the NC is probably the most studied developmental EMT.

The progenitors of the mitral and tricuspid valves and the membranous interventricular septum in the heart arise by an epithelial-mesenchymal cell transformation (EMT) from embryonic endothelial cells. Experiments using collagen gel cultures to mimic the three dimensional environment in the embryonic heart cushions showed that EMT was triggered by an inductive stimulus produced by the adjacent myocardium and that myocardium from a nontransforming region was insufficient to induce transformation. Studies using chick embryos have demonstrated distinct and sequential roles for two isoforms of TGFβ, Bone Morphogenetic Proteins, and roles for several TGFβ-family receptors in this EMT. Additional studies have identified at least two separate transcription factors required for EMT, Slug and Mox-1. The complexity of the inductive signal is not yet fully understood, but recent studies have shown roles for several Wnt proteins and a requirement for signaling by extracellular hyaluronan. The embryonic heart provides an experimental model of relevance to congenital heart diseases that are likely to continue to provide novel insight into the regulation of EMT as a normal process of development.

As a member of the Phylum, Cnidaria, hydra is organized a simple gastric tube with a head and foot pole. The entire body wall of hydra is organized as a epithelial bilayer with an intervening extracellular matrix (ECM). The major components of hydra ECM are highly conserved and reflect those seen in vertebrate systems. These components include laminin, collagen type IV, and a fibrillar collagen that is similar to a vertebrate type I/II class. The supramolecular organization of hydra ECM is seen as two basal lamina containing laminin and collagen type IV (one associated with the basal plasma membrane of the ectoderm and endoderm) with a central interstitial-like matrix containing fibrillar collagens. Because of the unique biophysical properties of hydra ECM, decapitation of hydra (or any wound to the bilayer) results in retraction of the matrix from the wound site. While the epithelial bilayer will seal within one hour, the matrix remains retracted resulting in a bilayer lacking an intervening ECM. This triggers an upregulation of matrix component mRNA within 3 hours of wounding and de novo biogenesis of hydra ECM that is completed within 24–72 hours from the initial time of decapitation or wounding. While the ECM of hydra is symmetrical (two basal laminin to the periphery of the central interstitial matrix), the synthesis of matrix components from the epithelium is asymmetrical. For example, laminin is secreted from the endoderm while collagen type IV and hydra fibrillar collagen (Hcol-I) are both secreted from the ectoderm. The timing of matrix component secretion is also irregular in that laminin and collagen type IV are secreted and integrated within the newly forming basal lamina within 6–12 hours of decapitation or wounding while fibrillar collagen is not secreted until at least 24 hours.

The sea urchin has been an instructive animal for studies of gene regulation in development, morphogenesis, and cell migration. This is in part due to their convenient external development, their ease in culturing, and their marvelous transparency that makes them optically accessible for many developmental and cellular events. The embryo displays a multitude of complex movements and features, but involves relatively few cells (< 500 during gastrulation). The embryo is resilient to micromanipulation studies whereby cells or portions of tissues may be readily microinjected, transplanted, or photo-ablated to test mechanistically the crafting of the embryo. The whole genome project, its correlated EST identification and arrays (see http://sugp.caltech.edu), combined with the simple technology of introducing exogenous genes, reporters, mRNA, morpholinos or over-expressed proteins prove to be a powerful combination of capabilities with the nearly limitless number of embryos (several million per adult female) make the biochemistry and molecular biology of manipulated embryos readily available.[] Finally, its status as a basal deuterostome, representing an early branch in the evolution of vertebrates, makes its molecular and cellular changes ripe for comparison in understanding the origin of body plan, embryonic mechanism, gene regulation and function.

Change of epithelial cell fate occurs in developmental, physiological, and pathological processes. While the initiation and outcome of the various processes may differ, many of the cellular and molecular controls are common. Using gastrulation as a model, we describe in this chapter the molecular genetics of cell shape changes of the epithelial cells in the blastoderm. The columnar epithelial cells in the ventral region, which are destined to become mesodermal precursors, behave differently from cells in other regions of the early embryo and invaginate to the appropriate position during gastrulation. Genetic studies point to the involvement of the region specific transcription factor Snail and the ubiquitous adherens junctions and cytoskeleton. How cell fate determinants turn on ubiquitous machineries to achieve the coordinated cell movements during gastrulation is being elucidated and is a fascinating area of research that attracts the attention of scientists from various disciplines.

Successful cutaneous wound repair occurs in a series of tightly coordinated and overlapping steps: (1) inflammation and clot formation, (2) keratinocyte activation and migration, (3) remodeling of the basement membrane and extracellular matrix, and (4) dermal and epidermal maturation. During the final three stages of cutaneous wound healing, restoration of an intact epidermis occurs via a complex process termed reepithelialization. In this chapter, we focus on the process of wound reepithelialization, emphasizing the resemblance of reepithelialization to epithelial-mesenchymal transition (EMT) occurring during development and tumor progression. Based on the many morphologic and molecular similarities between the two processes, we propose that wound reepithelialization represents a partial and reversible EMT.

Epithelial-mesenchymal transition (EMT) is a type of epithelial plasticity that is characterized by long-lasting morphological and molecular changes in epithelial cells as a result of transdifferentiation towards a mesenchymal cell type. To detect possible phenotypic transitions in human cancer, surgical pathology is a useful medical discipline, examining surgical or biopsy material at the microscopic and ultrastructural level. The expression in a particular tumor of epithelial and mesenchymal markers is evaluated by means of immunohistochemistry or in situ hybridization, and this could, besides directing to a correct diagnosis, substantiate a possible transdifferentiation. Whereas EMT occurs in several stages of embryonic development and can be readily induced in (cancer) cell lines in vitro, in human cancer the phenomenon is rarely encountered. Carcinosarcoma is the tumor best studied, in which monoclonality of both epithelial and mesenchymal cell components strongly favors an EMT. A challenging hypothes is considers EMT as a more general event, providing an additional survival advantage in all types of carcinoma. By means of EMT the epithelial tumor cells would transdifferentiate into myofibroblasts that lose their malignant phenotype but constitute the desmoplastic stroma which is essential for tumor growth, invasion and metastasis.

Intercellular adhesion and communication in mammalian epithelial cells occurs via special ized junctional complexes, which include tight junctions, adherens junctions, desmosomes, and gap junctions (Fig. 1).[] Desmosomes are unique among these junctions, as they are coupled to the intermediate filament (IF)-based cytoskeleton. These form stable complexes that facilitated the ultrastructural and biochemical characterization of desmosomes but also made progress in the molecular organization of these junctions more challenging.[]–[] Although the individual components that make up a desmosome are now fairly well established, we are just beginning to appreciate how desmosomes are assembled into highly regulated and dynamic adhesive units.