Perspectives for the Future

A deeper understanding of the integration of cells into tissues in complex organisms will draw on insights and techniques from virtually all subdisciplines of molecular cell biology—biochemistry, biophysics, microscopy, genetics, genomics, proteomics, and developmental biology—together with bioengineering and computer science. This area of cell biology is undergoing explosive growth.

An important set of questions for the future deals with the mechanisms by which cells detect and respond to mechanical forces on them and the extracellular matrix, as well as the influence of their three-dimensional arrangements and interactions. A related question is how this information is used to control cell and tissue structure and function. These issues involve the fields of biomechanics and mechanotransduction. Future research should give us a far more sophisticated understanding of the roles of the three-dimensional organization of cells and ECM components, and the forces acting on them under normal and pathological conditions, in controlling the structures and activities of tissues. Applications of such understanding will provide new methods to explore basic cell and tissue biology as well as improved technologies for the search for novel therapies for disease.

Although junctions play a key role in forming stable epithelial tissues and in defining the shapes and functional properties of epithelia, they are not static. Remodeling, in terms of replacement of older molecules with more recently synthesized molecules, is ongoing, and the dynamic properties of junctions open the door to more substantial changes when necessary (the epithelial-to-mesenchymal transition during development, wound healing, extravasation of leukocytes, etc.). Understanding the molecular mechanisms underlying the relationship between stability and dynamic change will provide new insights into morphogenesis, maintenance of tissue integrity and function, and response to (or induction of) pathology.

Numerous questions relate to intracellular signaling from CAMs and adhesion receptors. Such signaling must be integrated with other cellular signaling pathways that are activated by various external signals (e.g., growth factors) so that the cell responds appropriately and in a coordinated fashion to many different simultaneous internal and external stimuli. It appears that small GTPases participate in at least some of the integrated pathways associated with signaling between cell junctions. How are the logic circuits constructed that allow cross talk between diverse signaling pathways? How do these circuits integrate the information from these pathways? How is the combination of outside-in and inside-out signaling mediated by CAMs and adhesion receptors merged into such circuits?

We can expect ever-increasing progress in the exploration of the influence of glycobiology (the biology of oligo-and polysaccharides) on cell biology. The importance of specialized GAG sequences in controlling cellular activities, especially interactions between some growth factors and their receptors, is now clear. With the identification of the biosynthetic mechanisms by which these complex structures are generated and the development of tools to manipulate GAG structures and test their functions in cultured systems and in intact animals, we can expect a dramatic increase in our understanding of the cell biology of GAGs in the next several years. There is still much to learn about the biosynthesis, structures, and functions of many other glycoconjugates, such as the O-linked sugars on dystroglycan that are essential for its binding to its ECM ligands. The new subspecialty of glycomics has recently been flourishing and will contribute to our future understanding of glycobiology. Glycomics, like genomics and proteomics, uses high-throughput tools, such as mass spectrometry, to perform large-scale analyses of the structures of and changes in the wide range of sugar-containing molecules in cells and tissues.

A structural hallmark of CAMs, adhesion receptors, and ECM proteins is the presence of multiple domains that impart diverse functions to a single polypeptide chain. It is generally agreed that such multidomain proteins arose evolutionarily by the assembly of distinct DNA sequences encoding the distinct domains. Genes encoding multiple domains provide opportunities to generate enormous sequence and functional diversity by alternative splicing and the use of alternative promoters within a gene. Thus, even though the number of independent genes in the human genome seems surprisingly small in comparison with other organisms, far more distinct protein molecules can be produced than predicted from the number of genes. Such diversity seems very well suited to the generation of proteins that take part in specifying adhesive connections in the nervous system, especially in the brain. In fact, several groups of proteins expressed by neurons appear to have just such combinatorial diversity of structure. They include the protocadherins, a family of cadherins in which many proteins are encoded by each gene (14–19 for the three genes in mammals); the neurexins, which comprise more than a thousand proteins encoded by three genes; and the Dscams, members of the IgCAM superfamily encoded by a Drosophila gene that has the potential to express 38,016 distinct proteins owing to alternative splicing. A continuing goal for future work will be to describe and understand the molecular basis of functional cell-cell and cell-matrix attachments—the “wiring”—in the nervous system and how that wiring ultimately permits complex neuronal control and, indeed, the intellect required to understand molecular cell biology.