GENE-REGULATION OF CELL-ADHESION MOLECULES IN NEURAL MORPHOGENESIS

A mounting body of evidence suggests that cell-cell adhesion molecules (CAMs) play critical roles in morphogenetic patterning and in laying down the initial tissue scaffold of the nervous system. Perturbations of CAM binding can lead to altered tissue pattern and interruption of tissue interactions to altered patterns of CAM expression. The combine d factors that regulate the expression of CAMs and that drive early ne ural development are, however, largely unknown. We have hypothesized t hat the coordinate expression of homeobox (Hox) and paired box (Pax) t ranscription factors in various axes of the body plan leads to differe ntial expression of particular CAM genes. Following this hypothesis, w e have characterized the promoters and other regulatory regions of a n umber of genes specifying CAMs and have identified cis-regulatory elem ents that bind and respond to Hox and Pax proteins. Our recent experim ents in vitro indicate, for example, that transcription factors encode d by Hox and Pax genes bind to specific DNA sequences in the N-CAM pro moter and activate expression of the N-CAM gene. Experiments on transg enic mice carrying either the wild-type N-CAM promoter or a variant wi th mutations in the homeodomain binding sites (HBS) linked to a lac-Z reporter gene indicate that interactions with these elements are impor tant in establishing and maintaining N-CAM expression in the spinal co rd. We have also examined the regulatory sequences controlling express ion of the gene for the neuron-glia adhesion molecule (Ng-CAM). Unlike N-CAM, which is also expressed in many non-neural sites, Ng-CAM is re stricted to cells of the nervous system, After identifying this promot er for the Ng-CAM gene, we characterized a silencer region in the firs t intron of the gene that extinguishes the expression of Ng-CAM in fib roblasts but not in neuronal cells. Thus, a default mechanism can acco unt for the restriction of Ng-CAM expression to the nervous system. Th e silencer region contains five neural-restrictive silencer elements a nd a binding site for the Pax3 protein, which also appears to have sil encing activity. All of these findings suggest that Hox and Pax transc ription factors can have both activating and silencing functions in re gulating CAM gene expression. The general significance of these accumu lated observations is that they connect the place-dependent expression of gene products capable of direct morphoregulation to the function o f pattern-forming genes.