Cell-surface area codes: mobile-element related gene switches generate precise and heritable cell-surface displays of address molecules that are usedfor constructing embryos

We present an updated area code hypothesis supporting the proposal that cel l surface display of seven-transmembrane olfactory receptors, protocadherin s and other cell surface receptors provide codes that enable cells to find their correct partners as they sculpture embryos. The genetic mechanisms th at program the expression of such displays have been largely unknown until very recently. However, increasing evidence now suggests that precise devel opmental control of the expression of these genes during embryogenesis is a chieved in part by permanent and heritable changes in DNA. Using the develo ping immune system as a model, we discuss two different types of developmen tally programmed genetic switches, each of which relies on recombination me chanisms related to mobile elements. We review new evidence suggesting the involvement of mobile element related switch mechanisms in the generation o f protocadherin molecules, and their possible involvement in the control of expressions of olfactory receptors. As both recombinase and reverse transc riptase mechanisms play a role in the switching of the immunoglobulin genes , we searched the databases of expressed sequence tags (dbEST) for expressi on of related genes in other tissues. We present data revealing that transp osases and reverse transcriptases are widely expressed in most tissues. We also searched these databases for expression of env (envelope) gene product s, stimulated by provocative results suggesting that these molecules might function as cellular address receptors. We found that env genes are also ex pressed in large numbers in normal human tissues. One must assume that thes e three different types of mobile-element-related messenger RNA molecules ( transposases, reverse transcriptases, and env proteins) are expressed for u se in functions of value in the various tissues and have been preserved in the genome because of their selective advantages. We conclude that it is possible that many specific cell lineage decisions a re made and remembered by means of genetic switches similar to those that c ontrol the immunoglobulin and protocadherin and, probably, the seven transm embrane/olfactory gene families. We also conclude that complex genetic prog rams utilizing mobile-element-related genes program these events.