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Organogensis


VI.1 COORDINATORS
VI.2 PARTICIPANTS
VI.3 SUMMARY
VI.4 INTRODUCTION
VI.5 SPECIFIC AIMS
VI.6 BACKGROUND AND SIGNIFICANCE VI.7 THEORETICAL FRAMEWORK
VI.8 PRELIMINARY RESULTS
VI.9 RESEARCH DESIGN AND METHODS
VI.10 RELATIONSHIP TO CYTOSKELETON (PROJECT 2) AND BIOLOGICAL NETWORKS (PROJECT 1)
VI.11 TIMELINE

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VI.6.ii Interplay of Physical and Genetic Mechanisms in Organogenesis:

Embryos and tissues develop forms which express highly complex, genetic programs. Nevertheless, embryos, organs, and healing and regenerating tissues assume many forms resembling those that physics produces in nonliving materials. Often genes determine morphogenesis by mobilizing physical forces and properties. We will describe a range of mechanisms underlying or contributing to tissue morphogenesis, which living and nonliving materials shared and which thus allow modeling that uses variations of the methods of computational physics. We call such processes "generic" (Newman and Comper, 1990). The systems and mechanisms we describe represent a sample of the research of Consortium members.

Single cells, as independent signal-processing units, interact with their environment (including diffusible chemicals and extra cellular matrix, ECM) and communicate with each other through their membranes. Findings in material science suggest that physical properties such as the adhesiveness of the cell surface, the viscoelasticity of the intracellular milieu and the extracellular matrix, and the cell’s biosynthetic response ("excitability"), all of which are genetically regulated, can alter in response to external stimuli and can determine macroscopic tissue properties and behavior.

Physical mechanisms depending on the material properties of cells and tissues profoundly affect morphogenesis. These material properties depend on the gene products expressed by the cells and tissues, as well as on other components, such as water and ions, which gene products typically control. Thus looking at tissue morphogenesis as a physical phenomenon and looking at it as a genetic phenomenon are compatible. Changes in gene expression mobilize many, if not most, of the physical processes we consider, although many immediate signals and biochemical modifications at the cellular level may not require direct genetic instructions.

The following subsections briefly describe how chemical reaction, diffusion, and ECM deposition generate extracellular signals; how cells respond to these signals and undergo patterned changes in functional or adhesive state; and how sequential changes of cells’ surface properties can, in turn, lead to modifications of the chemical environment and ECM configuration, thus driving morphogenetic behavior.

VI.6.ii.a Cell Adhesion:

Cell adhesion is necessary for multicellularity. Its alteration is also central to many, morphogenetic changes. Many types of cell-surface proteins are adhesive under various conditions and modern organisms use several different adhesion mechanisms. Experimentally, a mixture of cell types with different quantities or types of adhesion molecules on their surfaces will sort out into islands of more cohesive cells within lakes of their less cohesive neighbors. Eventually, through random cell movement, the islands coalesce to establish an interface across which cells do not intermix (Steinberg, 1998) (Fig. VI.1a). Two or more differentially adhesive cell populations present within the same tissue mass can self-assemble into multilayered structures, comprising distinct non-mixing compartments. The phenomenon resembles what happens when we pour two immiscible liquids, such as oil and water, into the same container.

VI.6.ii.b Chemotaxis and Haptotaxis:

Cells are capable of generating protrusive movements by internal mechanisms (see cytoskeleton section, Project 2) which allow them to move through their surrounding environment. Although a cell's intrinsic polarity may cause it to move in a preferred direction relative to its own symmetry, its direction of movement relative to other cells in the embryo will be random unless it experiences external signals or forces. Diffusible chemical signals in the form of polypeptide growth factors can cause cells to migrate preferentially in a given direction, typically up the gradient of the factor, in chemotaxis. Alternatively, bound molecules, either on the surfaces of adjacent cells or in the extracellular matrix, can provide adhesive gradients that guide cell movements in a preferred direction, in haptotaxis.

VI.6.ii.c Epithelial and Mesenchymal Tissues:

Tissues have two main types of structural organization, epithelia in which the cells form layers, with tight lateral connections and direct cell-cell contacts, and mesenchyme, in which the cells form a three-dimensional structure usually supported by extracellular matrix (ECM). Epithelial sheets can bend, evert, invaginate, and form placodes, cysts, and tubules, depending on local and polar expression of adhesive molecules (Newman, 1998) (Fig. VI.1f). The physics of fluids (confined to a plane) can account for many details of epithelial sheet morphogenesis (Gierer, 1977; Mittenthal and Mazo, 1983). embryonic epiblast and vascular structures are examples of specialized epithelia, while the embryonic mesoblast and the skeletogenic tissue of the vertebrate limb bud connective tissue are typical mesenchymes.

VI.6.ii.d Epithelia and Cell Polarity:

Epithelioid cells sometimes have uniform adhesive properties over their entire surface (e.g. the blastomeres of the early mammalian embryo). The cells of many epithelioid, and all epithelial tissues, however, are polar in their properties, notably adhesion (Rodriguez-Boulan and Nelson 1993). The targeting of adhesive molecules or anti-adhesive molecules to specific regions of the cell surface can have dramatic consequences. A tissue mass consisting of motile epithelioid cells that are non-adhesive over portions of their surfaces will readily develop cavities or lumens. As a result of random cell movement, or loss of cells adjoining the nonadherent surfaces of neighboring cells, such spaces can come to adjoin one another. Lumen formation may therefore have evolutionary origins as a simple consequence of differential adhesion in cells that express adhesive properties in a polarized fashion (Fig VI.1b). In most existing organisms, however, other cellular mechanisms, such as the contraction of apical actin filaments in a group of cells in a localized domain of an epithelial sheet, contribute to, and may even initiate, lumen formation (Grant et al., 1991; Lincz et al., 1997).

VI.6.ii.e Mesenchyme and Extracellular Matrix:

In contrast to epithelioid and epithelial tissues, in which cells directly adhere to one another over a substantial portion of their surfaces, connective tissues consist of cells suspended in an extracellular matrix (ECM). Additional morphogenetic mechanisms depend on changes in the distance between cells, the effects of cells on the organization of the ECM, and the effects of the ECM on the shape and cytoskeletal organization of cells that typically occur in connective, but not epithelioid, tissues. in epithelioid tissues, immiscible boundaries can develop in connective tissues, such as the interface between the flank of a developing vertebrate embryo and an emerging limb bud (Heintzelman et al., 1978). formation of elaborate cell-ECM adhesive structures in developmentally mature connective tissues permits physical forces originating within cells to contribute to tissue morphogenesis (Newman and Tomasek, 1996). In particular, fibers can transmit the intracellular forces necessary for cell shape changes and migration to the surrounding cells and ECM, mechanically stressing the whole tissue (Beloussov et al., 1975; Grinnell, 1994; Ingber et al., 1994). In such cases the tissue no longer exhibits liquid-like behavior (since the cells are not independently mobile), but rather behaves as an elastic solid.

VI.6.ii.f Mesenchymal Condensation:

In mesenchymal condensation, which is often transient in development, mesenchymal cells, initially dispersed in a matrix, move closer to one another. Condensations generally progress to other structures, such as feather germs (Chuong, 1993), cartilage or bone (Hall and Miyake, 1992; 2000; Newman and Tomasek, 1996), or, after converting to epithelium, kidney tubules (Ekblom, 1992) (Fig. VI.1d). In vitro studies of limb bud precartilage mesenchyme suggest that differential adhesion to, and accumulation at sites of, altered ECM can initiate condensation (Frenz et al. 1989a; 1989b), in line with predictions from theoretical models (Graner and Glazier, 1992; Graner, 1993; Glazier and Graner, 1993). Moreover, recent studies provide direct evidence that reaction-diffusion-based pattern formation changes the local cellular microenvironment during condensation in vitro (Miura and Shiota, 2000a; 2000b; Miura et al., 2000), supporting earlier suggestions (Newman and Frisch, 1979; Newman et al., 1988; Newman, 1996) (Fig. VI.1e). Here, a physical process possibly involved in the origin of body plan morphology acts locally during organogenesis. experiments (Hall and Miyake, 1992; 2000; Newman and Tomasek, 1996) support a mechanism for mesenchymal condensation in which localized patches or domains of extracellular matrix form in an initially homogeneous tissue, by one of several pattern-forming mechanisms. The cells respond to the locally changed matrix by adhering to one another at these sites. Although no cell sorting takes place, differential adhesion occurs. This mechanism requires that the cell response time to the altered matrix be faster than the dispersal of the matrix, a reasonable assumption ( Kiskowski et al., 2002).

VI.6.ii.g Cell Excitability:

Because cells are metabolically active (both directly secreting and absorbing extracellular chemicals and secreting enzymes which may degrade or stabilize extracellular chemicals) and experience positive feedback, they may cause temporal or spatial oscillations in chemical concentrations (Mikhailov, 1990; Goldbeter, 1996). The capacity of single cells or cell aggregates to generate oscillations of gene products or metabolites, and for external effects to trigger such oscillations is a major mechanism of patterning. the periodic expression of a molecule linked to the cells' adhesive properties in a confined growth zone of an embryo or organ primordium. If the expression of such an adhesivity regulatory factor has a different period from the cell cycle, cells will be born with periodically recurring adhesive states, and a spatial array of alternating tissue compartments or segments will form (Newman, 1993) (Fig. VI.1c). A mechanism of this sort may be at work in vertebrate somitogenesis (Palmeirim et al., 1997).