The area-code hypothesis: the immune system provides clues to understanding the genetic and molecular basis of cell recognition during development.

Numerous studies of embryogenesis have provided evidence for highly specific cell-surface recognition phenomena. These include both the interactions of neighboring cells and the specific cellular migrations which occur as the developmental program of the embryo progresses. The area-code hypothesis elaborated here is an attempt to provide a framework for understanding cell-recognition phenomena in development. This hypothesis is based on extensive genetic, molecular, and cellular studies of the immune system. These studies suggest that the following events occur during the differentiation of antibody-producing cells. (1) Somatic cell lines of antibody-producing cells undergo a modification of their DNA as they become committed to synthesize a particular type of antibody molecule. This chromosomal modification event is probably a DNA translocation which leads to a somatic rearrangement of certain antibody genes. (2) In each of the specific cell lineages the new arrangement of DNA is inherited by all subsequent generations of cells. (3) The developmental programs which control these genetic alterations may be employed in a programmed and reproducible fashion. This programming of antibody development is suggested because different embryos appear to become committed to the production of identical antibody molecules in the same developmental sequence. (4) Antibody molecules are initially displayed on the cell surface where they serve as highly specific receptors to trigger the cell to proliferate and differentiate upon interacting with appropriate external molecular signals. (5) Antibody-producing cells display combinations of different molecules on their surfaces which cause each of a very large number of different cells to interact differently with their environment. (6) The genes which code for many of these cell-surface molecules are organized into multigene families. These observations as well as information from other developmental systems have led us to propose the area-code hypothesis. This hypothesis is concerned with the structure, function, and regulation of cell-surface molecules that mediate recognition phenomena during embryogenesis. Area-code molecules are cell-surface molecules which are involved in the specific recognition phenomena during growth and development. These molecules provide cells with distinct cell-surface addresses or pheno-types, and provide the basis for the specificity in cell-cell recognition during cell migrations and cell-cell interactions, as well as serving as receptors for diffusible differentiation signals. The area-code hypothesis has 3 main postulates. (i) There is a progressive display of specific combinations of area-code molecules on the surfaces of cells during development. (ii) The genetic programs which determine the specific expression of area-code molecules are in part controlled by DNA modifications. These chromosomal modifications are believed to channel cells into specific lineages with progressively restricted developmental options. (iii) Many of the area-code systems are organized into multigene families. Rapid evolutionary increases in complexity may proceed by the duplication and subsequent independent evolution of multigene families. In short, many of the remarkable events which occur during the development of the immune system may form a basis for understanding other developmental systems. Some experimental approaches toward testing this hypothesis are discussed.