My overall goal is to understand how the neocortical area map develops in the embryonic and early postnatal mammalian brain. The prevailing model of how area patterning is initiated in the embryo is based on research in the smooth-brained or """"""""lissencephalic"""""""" mouse, yet studies that support this model are aimed at revealing how the area map is established in mammals in general. Recent discoveries regarding the generation of cortical neurons in gyrencephalic mammals, however, suggest problems with applying the mouse model to these species. A major concern in the field, therefore, is that there can be no """"""""general"""""""" model of neocortical patterning. I propose here to test whether the current model holds for area map development in the gyrencephalic cortex of the ferret. First, I will verify that the ferret cortical primordium (CP) has similar signaling centers to those that pattern the cortex in the mouse. I predict this will be so, given that one center has already been identified in humans. Further, I will identify which of the gene and protein expression patterns that delineate areas in the postnatal mouse cortex also delineate area boundaries in ferret. In the mouse telencephalon, a rostral patterning center (RPC) releases Fibroblast Growth Factor (FGF) 8, a morphogen that disperses in a gradient across the CP supplying positional values to cortical progenitor cells. I expect the embryonic ferret cortex to have an RPC, which patterns both cortical and subcortical structures. In utero microelectroporation (IUME) will be used in live ferret embryos to manipulate levels of FGF8 at the RPC, and to introduce new sources of FGF8 in the CP. The area map will be examined in the pups at 3 weeks, using gene and protein expression patterns to identify area boundaries. If FGF8 controls the ferret area map, as in the mouse, then augmenting the rostral FGF8 source will shift area boundaries caudally, enlarging rostral areas, and shrinking caudal areas. Depleting the source will have opposite effects, and introducing a new source of FGF8 will duplicate areas. This project is designed to address a major stumbling block in the field of cortical development, and to (re)introduce the ferret as a species in which to investigate the mechanisms that pattern the neocortical area map. A full appreciation of human cortical development in the embryo will aid in understanding several major human neurological and psychiatric disorders with a strong developmental component.
The neocortex controls higher brain functions, such as perception, memory and planning, which are distributed among different areas. Basic molecular mechanisms that set up the area map in mouse neocortex are known. Whether the same mechanisms pattern ferret cortex, more similar to human cortex, will be tested. Results should shed light on human disorders caused by defects in cortical development.