The long-term goal of these studies is to understand how the basic functional organization of the mammalian cerebral cortex - the cortical area map - arises in development. We are testing a model in which the area map is set up by discrete signaling centers. One such center is the cortical hem, generating Wingless-lnt (WNT) and Bone Morphogenetic Protein (BMP) proteins. Our primary hypothesis is that the cortical hem regulates development of the area map along the medial/lateral (M/L) axis. In addition, preliminary findings indicate new roles for the hem via its generation of a rich variety of cell types, transient and permanent, neuronal and non-neuronal.
In Aim 1, we will fate map the hem using the WNT3a locus to direct Cre expression to the hem. The resulting mouse line will be crossed with reporter mice, carrying marker genes flanked by IoxP sites, in the offspring, WNT3a-expressing hem cells and their progeny will be permanently marked. Hem-derived cells will be definitively characterized with markers of cell division, cell type, cell death and connectivity. Their development and striking migratory behavior will be followed in fixed tissue and living slices;cues that direct their migration will be explored.
In Aim 2, we will ablate the cortical hem utilizing the WNT3a locus and Cre-lox recombination to direct expression of a cellular toxin to the hem. Cortices in which the hem is entirely or partially ablated, or in which hem cells are ablated mosaically ("hem hypomorphs") will be analyzed at embryonic and postnatal ages. Gene expression patterns, neurochemistry, cytoarchitecture and functional connectivity will be used to identify shifts or loss of M/L patterning in the cortex. With similar techniques, we will determine the effects of the loss of hem-derived cells. A possibility is defective cortical lamination, which could indicate that the hem directs cortical patterning along two axes.
Aim 3 will focus more specifically on the contributions of WNT and BMP signaling from the hem. Using classic mouse genetic approaches, we will evaluate the effects of different, lower levels of BMP signaling on M/L cortical patterning. Next, we will attempt to rescue particular defects that result from hem loss by replacing WNT and BMP signals, utilizing in utero electroporation-mediated gene transfer. Together these studies should clarify normal development of the cerebral cortex, and shed light on the possible causes of human cortical malformations.
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