Overarching concepts in development

Signalling between embryonic cells and tissues

Within the developing blastocyst, the position of cells relative to each other leads to epigenetic change. The acquisition of cell polarity is fundamental, because this specifies apical and basolateral domains, cell surface specializations, the positioning of intracellular organelles and cytoskeletal elements, and the position and nature of cell–cell junctions. The establishment cell junctional complexes between the outer, polarized, cells of the morula within the zona pellucida are the earliest embryonic cell interactions. The signals received by adjacent cells induces a change in their subsequent behaviour. Cellular signalling between cells and tissues occur via: direct cell–cell contact (gap junctions); cell adhesion molecules and their receptors; extracellular matrix molecules and their receptors; and growth factors and their receptors. The production of a basal lamina by epithelial cells (containing, e.g., laminin and fibronectin) and its attachment to underlying extracellular matrix molecules (collagen, proteoglycans and glycosaminoglycans) synthesized by mesenchyme cells constructs the tissues in which reciprocal signalling occurs ( Fig. 11.1 ). In most developing tissues an epithelium and its basal lamina are supported by underlying mesenchymal cells, each contributing to developmental interactions. However, there are a few sites where two epithelial layers, a special epithelium and an endothelium, generate a shared basement membrane to which both epithelial phenotypes contribute. This arrangement is seen between type-1 pneumocytes and endothelium in the developing lung alveoli; between the podocytes and endothelium in the glomerulus of the developing kidney; and between astrocyte end feet and pial-derived endothelium in the developing brain ( Fig. 11.2 ).

Combinations of all of these signalling routes are involved in development and their perturbation may result in developmental aberration. The transient production of, e.g., 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. 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; and mutations in fibrillin are associated with Marfan syndrome

Growth factors are distinguished from extracellular matrix molecules. They can be delivered to, and act on, cells in a variety of ways, namely: endocrine, autocrine, paracrine, intracrine, juxtacrine or matricrine ( Fig. 11.3 ). 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 beta, or attached to a binding protein, in the case of insulin-like growth factors.

Other signalling mechanisms occurring between these cell arrangements include the transduction of the biomechanics of mesenchyme cell synthesized matrix. Stiffness of the matrix leads cells towards an osteoblastic developmental phenotype, whereas soft matrix leads to an adipocyte lineage ( ). Endogenous electrical fields are also believed to have a role in cell–cell communication and 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 inter-rhombomeric boundaries.

The spatial and temporal distribution of a variety of cell adhesion molecules has been localized in the early embryo and displayed within the 3D tissue arrangement of embryos at a variety of stages (MGI mouse gene expression data search: eMAGE ). The temporal appearance of these molecules correlates with a variety of morphogenetic events that involve cell aggregation or disaggregation.

It is important to realize that while developmental studies on laboratory species and in vitro studies of animal tissues indicate the range of factors operating in embryos, the spatial and temporal expression of these factors in human embryos will be different. Figure 8.2 illustrates the temporal differences in external features between human and some animal species. Differences in heterochrony (the time at which genes are expressed and specific structures develop), are easily appreciated between mammals and marsupials, where marsupial embryos are born with facial and upper limb development well in advance of mammals of a similar developmental age ( ). Although not so extreme, differences in heterochrony are significant between human and mouse embryos and any extrapolation of animal developmental sequences to human development should be avoided. Somite generation frequency is 5 hours in humans and 2 hours in mice, and other processes, such as progenitor cell population expansion, have different time lines, e.g. generation of motor neurones takes 2–3 weeks in humans but a few days in mice ( ). The way in which embryonic cells and tissues count time is not yet clear, but analyses and correlation of specific heterochronic interspecies differences are now being investigated at the molecular level.