Our lab is interested in fundamental mechanisms governing development of the cerebral cortex. The cortex is the largest structure in the brain, essential for the intellectual functions that we humans pride ourselves on. The cerebral cortex has to solve several problems during development: it must be correctly patterned, it must obtain the proper complement of cells of distinct types, and finally all those cells have to get wired up just right in order to work properly. Whereas the cortex is complex, it provides several advantages as a genetic system for studying neuronal development.
1. Neurons of the cortex are not formed in the cortex; instead, they are derived from dividing cells located in specialized proliferative regions far away from the cortex. The dividing “progenitor” cells form postmitotic cortical neurons in a fixed sequence.
2. Postmitotic cortical cells migrate long distances away from the proliferating cells into the cortex before differentiating. Therefore, steps of mitotic and postmitotic neuronal development occur in different places.
3. A surprisingly large number of mutations, affecting humans or mice, disrupt specific steps in cortical development. These mutations affect the size and shape of the cerebral cortex, and often result in the accumulation of cortical cells in abnormal locations reflecting the site of action and the function of the gene involved. In humans, these genetic disorders result in mental retardation, seizures, and problems with coordinated movement and language.
We have used positional cloning to identify several genes required for the normal development of the cerebral cortex in humans and mice. An unexpected finding is that many of the genes that are essential for human cortical development were targets of evolutionary selection in the primate lineage leading to humans, suggesting that changes in some of these genes help define our brain as uniquely human. Ongoing work is mapping and cloning other loci that result in a malformed cortex or that produce subtler defects in language or social interactions (e.g., autism). Using genomic approaches we are also hunting for genes that pattern the cortex or that distinguish our “left” and “right” brain, which have different roles in language and perception. We are also using molecular biological and biochemical means to analyze the functions of the cloned proteins, in order to trace signal transduction cascades from the cell surface to the cytoskeleton.
|
Harvard University Home / GSAS Home / HMS Home 
