Tissue interactions

There are two types of cell and tissue interaction, namely, permissive and instructive.

In a permissive interaction, a signal from an apposing tissue is necessary for the successful self-differentiation of the responding tissue. This means that a particular cell population (or the matrix molecules secreted by the cells that it contains) will maintain mitotic activity in an adjacent cell population. Since a variety of different cell populations may permit a specific cell population to undergo mitosis and cell differentiation, no specific instruction or signal which may limit the developmental options of the responding tissue is involved: this signal therefore does not influence the developmental pathway selected and there is no restriction. The responding tissue has the intrinsic capacity to develop, and only needs appropriate environmental conditions in order to express this capacity. Permissive interactions often occur later in development, when a tissue whose fate has already been determined is maintained and stabilized by another.

An instructive (directive) interaction (induction) changes the cell type of the responding tissue, so that the cell population becomes restricted. Wessells (1977) proposed four general principles in most instructive interactions:

Principles 1–4 are exemplified during induction of the lens vesicle by the optic cup (p. 699). An example of principle 4 is the experimental association of chicken flank ectoderm with mouse mammary mesenchyme, which results in the morphogenesis of mammary gland-like structures: chickens do not normally develop mammary glands.

Tissue interactions continue into adult life and are probably responsible for maintaining the functional heterogeneity of adult tissues and organs. This is exemplified by the complex tissue heterogeneity, with sharply compartmentalized boundaries, that occurs in the oral cavity. The junctions between the mucosa of the vestibule and the lip, and between the vermilion border and the facial skin, are distinct boundaries of specific epithelial and mesenchymal differentiation, and are almost certainly maintained by continuing epithelial–mesenchymal interactions in adult life. Perturbation of these interactions throughout the body may underlie a wide variety of adult diseases, including susceptibility to cancer and proliferative disorders.

Signalling between embryonic cells and tissues

Cellular interactions may be signalled by four principal mechanisms: direct cell–cell contact; cell adhesion molecules and their receptors; extracellular matrix molecules and their receptors; growth factors and their receptors. Many of these mechanisms interact, and it is likely that combinations of them are involved in development. Figure 11.1 illustrates diagrammatically some ways by which mesenchymal cells could signal to epithelial cells. An additional set of identical mechanisms could operate for epithelial-to-mesenchymal cell signalling. Clearly, the complexity of these mechanisms will increase in reciprocal interactions; moreover, a single molecule may have different effects on epithelial and mesenchymal cells.

Fig. 11.1 The many ways by which mesenchyme cells could signal to epithelial cells. Precisely the same mechanisms can operate in reverse, i.e. epithelium to mesenchyme.

Direct cell–cell contact permits the construction of gap junctions, which are important for communication and the transfer of information between cells. The transient production of gap junctions is seen as epithelial somites are formed, between neuroepithelial cells within rhombomeres, and in the tunica media of the outflow tract of the heart. Endogenous electrical fields are also believed to have a role in cell–cell communication. Such fields have been demonstrated in a range of amphibian embryos, and in vertebrate embryos during primitive streak ingression. Neuroepithelial cells are electrically coupled, regardless of their position relative to interrhombomeric boundaries.

The spatial and temporal distribution of a variety of cell adhesion molecules has been localized in the early embryo. The appearance of these molecules correlates with a variety of morphogenetic events that involve cell aggregation or disaggregation, for example, an early response of groups of cells to embryonic inductive influences is the expression of cadherins, calcium-dependent adhesion molecules typically found in epithelial populations. Other molecules found in the extracellular matrix, e.g. fibronectin and laminin, inter alia can modulate cell adhesion by their degree of glycosylation. Self-assembly or cross-linking by matrix molecules may affect cell adhesiveness by increasing the availability of binding sites or by obscuring them.

Extracellular matrix molecules include localized molecules of the basal lamina, e.g. laminin, fibronectin, and much larger complex associations of collagen, glycosaminoglycans, proteoglycans and glycoproteins between the mesenchyme cells. Mutations of the genes that code for extracellular matrix molecules give rise to a number of congenital disorders, e.g. mutations in type I collagen produce osteogenesis imperfecta; mutations in type II collagen produce disorders of cartilage; mutations in fibrillin are associated with Marfan’s syndrome.

Growth factors are distinguished from extracellular matrix molecules. They can be delivered to, and act upon, cells in a variety of ways, namely endocrine, autocrine, paracrine, intracrine, juxtacrine and matricrine (Fig. 11.2). Many growth factors are secreted in a latent form, e.g. associated with a propeptide (latency-associated peptide) in the case of transforming growth factor β, or attached to a binding protein, in the case of insulin-like growth factors.

Fig. 11.2 Cells can also communicate by the reception, production and secretion of growth factors. A typical embryonic mesenchyme cell could receive and produce growth factors in this way.

Hox genes in development

Two related themes have emerged from experimental studies of development. First, that the control of embryonic morphology has been highly conserved in evolution between vertebrates and invertebrates, and second, that this control involves families of genes coding for proteins that act as transcriptional regulators.

The fruit fly, Drosophila, possesses eight homeotic genes that specify the structures developing on each body segment. These genes have been identified in vertebrates, raising the possibility that they have similar functions in development. They are termed homeobox genes, abbreviated to Hox in the mouse and HOX in humans, and are found on four clusters known as A, B, C and D. Individual genes are numbered from 1 to 13: 1 is a cephalic gene and 13 is a more caudally placed gene.

Homeobox genes are believed to be responsible, at least in part, for the evolutionary origin of the embryonic body plan (Robert 2001). Experimental study of transgenic animals in which the homeobox genes have been knocked out provide some evidence of their function: however, because developmental processes permit significant recovery from insult, some of the outcomes cannot be directly interpreted as demonstrating the effect of such gene loss.

Experimental approaches to embryology

One of the most exciting techniques to provide information on cell movements and fates during development is the use of chimeric embryos. Small portions of an embryo are excised and replaced with similar portions of an embryo from a different species at the same stage and the resulting development is then studied. This technique has been particularly effective using chick and quail embryos, because the nucleolus is especially prominent in all quail cells, whereas it is not prominent in chick cells, which means that quail cells may be easily identified within a chick embryo after chimeric transplantation (Le Douarin 1969). The technique has also confirmed the reciprocity of tissue interaction between the embryonic species, a phenomenon that had previously been illustrated, for a limited period, in co-cultures of embryonic avian and mammalian tissues. Somite development and vertebral formation have been studied in mouse–chick chimeras (Fontaine-Pérus 2000). The production in vitro, of human-animal chimeric cell lines is providing new ways of studying cellular pathways, as is the introduction of human artificial chromosome vectors into animal cells to study their interaction.