The experiments in this proposal test the hypothesis that distinct regions of the neuroepithelium in the mammalian telencephalic vesicle have unique cellular and molecular characteristics prior to and during the division of the vesicle into rudiments of the major subdivisions of the forebrain-the neocortex, the hippocampus, the basal ganglia, the olfactory bulbs, and the basal forebrain. Preliminary studies suggest that a region in the lateral wall of the mouse telencephalic vesicle can be recognized consistently between the 10th and 12th day of gestation based upon a number of criteria. The experiments described here will determine whether or not this zone is truly a discreet embryonic domain that prefigures forebrain regional differentiation. Initially, the distinct cellular character of the zone will be assessed by examining differences in cell proliferation, cell cycle, neurogenesis, neurite ingrowth, cell adhesion and cell movement. These experiments will be performed on fetal mice using DNA labeling techniques, immunocytochemical localization of neuron. specific markers and cell adhesion molecules as well as fluorescent dye labeling techniques. Additional experiments will determine whether this zone is also characterized by the unique expression of a transcription factor, the retinoic acid receptor, that might be involved in differential gene expression within the zone. Specific interactions between an identified population of axons projecting to the zone early in development-the olfactory axons-and the lateral zone will be explored. The hypothesis that these interactions are guided by coordinated expression of cell adhesion molecules, perhaps under the control of a common signal, will be evaluated. From these experiments it should be possible to determine whether or not a discrete population of cells in the neuroepithelium of the telencephalon can acquire regional identity before morphologically distinguishable subdivisions of the forebrain emerge, whether these regional distinctions are significant for establishing initial axon pathways, and whether the expression of developmentally regulated transcription factors can be correlated with this process. If this is the case, one can conclude that the initial division of the vesicle into rudiments of structurally and functionally distinct forebrain regions relies upon mechanisms similar to the segmental and compartmental processes known to play a role in pattern formation and regional differentiation at earlier stages of embryogenesis.
