B.A. Yale; Ph.D. M.I.T.
How does a simple sheet of dividing cells develop into the complex mammalian cerebral cortex, controlling higher brain functions such as perception, cognition and memory? We address this question for two different types of cortex, neocortex and the hippocampus.
Neocortex is divided into a map of functionally specialized areas, an organization that seems fundamental to how neocortex works. Across many mammalian species the relative positions of primary sensory and motor areas in the map are similar, suggesting that mechanisms generating basic features of the map are conserved. Using gene expression assays, mouse genetics and a novel method of gene transfer in mouse embryos in utero, we identified two embryonic signaling centers for the cortical primordium –conserved in mouse, ferret and chick. One, termed the “cortical hem”, produces powerful developmental signaling proteins of the WNT (Wingless/Int) and BMP (Bone Morphogenetic Protein) families, and is both necessary and sufficient for the formation of a hippocampus. Following on from these findings, we now want to discover the mechanisms that divide the hippocampus into distinct fields and direct their typical connections and functions.
The second signaling center is near the rostral cortical primordium and generates FGF proteins (Fibroblast Growth Factors), FGF8 and 17. These molecules disperse in gradients from the source, providing positional values to the cortical primordium and initiating map formation. Thus, if a new source of FGF8 is experimentally introduced into a mouse embryo near the original source, excess FGF8 pushes cortical area boundaries caudally. If the new source is at the opposite, caudal pole of the primordium, the dual (and dueling) signal sources create duplicate areas. We are now searching for genes downstream of FGF8 that regulate the features that characterize mature areas. A further goal is to determine how patterning mechanisms intrinsic to the neocortical primordium interact with emerging brain activity. Comparative studies of cortical development are planned to gain insight into how cortex is assembled in different species, and how cortical organization may have evolved.