The area code hypothesis revisited: olfactory receptors and other related transmembrane receptors may function as the last digits in a cell surface code for assembling embryos

Abstract

Recent evidence emerging from several laboratories, integrated with new data obtained by searching the genome databases, suggests that the area code hypothesis provides a good heuristic model for explaining the remarkable specificity of cell migration and tissue assembly that occurs throughout embryogenesis. The area code hypothesis proposes that cells assemble organisms, including their brains and nervous systems, with the aid of a molecular-addressing code that functions much like the country, area, regional, and local portions of the telephone dialing system. The complexity of the information required to code cells for the construction of entire organisms is so enormous that we assume that the code must make combinatorial use of members of large multigene families. Such a system would reuse the same receptors as molecular digits in various regions of the embryo, thus greatly reducing the total number of genes required. We present the hypothesis that members of the very large families of olfactory receptors and vomeronasal receptors fulfill the criteria proposed for area code molecules and could serve as the last digits in such a code. We discuss our evidence indicating that receptors of these families are expressed in many parts of developing embryos and suggest that they play a key functional role in cell recognition and targeting not only in the olfactory system but also throughout the brain and numerous other organs as they are assembled.

Figure 1

Hypothetical mechanism for the assembly of the precise topological map of glomeruli. A gradient of molecular affinities of olfactory receptors. Approximately, 1,000 molecularly distinct glomeruli are arranged in a topologically precise map in the olfactory bulb. This map is bilaterally symmetrical, but only one side is illustrated here. There are four distinct zones of glomeruli in the bulb (–50), illustrated here in various shades of red, yellow, green, and blue. Gradients of colors on glomeruli within each zone are used to suggest an orderly gradient of molecular affinities of the individual receptors. A stream of migrating neurons originates in a specific fate-mapped region of the subventricular zone (22). Cells migrate as streams with the growth cones of each contacting the cell ahead (21). Colors and gradients are used again to suggest that receptors on each cell differ in an orderly way so that neighboring cells have receptors that bind with the highest affinity to each other. After reaching the olfactory bulb, cells change their direction of migration and move toward the surface of the bulb where they generate periglomerular cells (22). The dendrites of these cells then form the targets for incoming growth cones of olfactory nerve axons. Hundreds of olfactory neurons bearing the same, specific, olfactory receptor converge on a single pair of bilaterally symmetrical glomeruli (–12). Their growth cones synapse with the dendrites of the periglomerular cells presumed to express the identical receptor. These homophilic interactions occur with the highest affinity. According to this hypothesis, receptors on neighboring glomeruli have closely related but different structures, hence are bound with a slightly lower affinity. Mitral/tufted cells also synapse with glomeruli but are not illustrated here.

Figure 2

Diagram of a region of human chromosome 17 that codes for two olfactory receptors. This figure, based on the work of Glusman et al. (46), illustrates one of many sequenced regions of chromosomes that code for olfactory receptors and also contain numerous mobile elements. Note the pattern of elements near the upstream control elements of the two olfactory receptor-coding regions (OR228 and OR 40). See the original publication for more details of this work. We hypothesize that some of these elements are used as genetic switches for the control of the expression of the 1,000 or more olfactory receptor genes. The mobile element-related and transposase mechanisms used could be evolutionarily related to those now known to control the expression of genes in the immune system. This would help explain how the olfactory system, like the immune system, expresses only one receptor gene in each stem cell. In both the olfactory and immune systems, such committed stem cells not only remember which receptor gene to express but also which one of the two alleles (30).