Christopher A. Walsh

What makes us human? It is the job of the human brain to change constantly in response to everything we learn. Yet it is ironically the genes that we inherit from our parents, and that our ancestors inherited from their ancestors, that reproducibly direct the development of a brain with this marvelous ability to change. It should be no surprise that mutations in the genes that construct our cerebral cortex, the seat of our highest cognitive functions, cause crippling consequences such as epilepsy, autism, and mental retardation or other learning disorders. Despite the recent advances in our understanding of the human genome, however, most genetic causes of these conditions remain unknown. Our lab is interested in identifying genes that direct the development of the cerebral cortex, not only because of their disease-related importance but also because they tell us about the normal development and evolution of the brain.

Although the cerebral cortex of the mouse and that of the human show microscopic similarities, the human cortex is 200 times larger and thrown into folds to increase its surface area, allowing more cortical neurons to fit inside our heads. How is the size of the cerebral cortex controlled? The cortex develops from progenitor cells deep in the brain, and the manner in which progenitors divide has profound consequences for the ultimate size of the cortex. Some progenitor cells divide to generate two dividing daughter cells and hence exponentially enlarge the progenitor population. In contrast,other cell divisions produce a neuron that leaves the layer and divides no further, and only one progenitor cell, causing a slower, linear increase in cell number. Control of the fates of these cell divisions hence controls cortical size. We found that the decision to divide or stop can be controlled by the protein beta-catenin. Too much beta-catenin causes the mouse cortex to become hugely enlarged and to develop folds that resemble the folds of the human cortex, because progenitors expand themselves more times before making neurons. In contrast, mutant mice with defects in the normal pattern of expression of beta-catenin have a small cortex.

Genes essential for normal human cerebral cortical size can be identified by studying families in which the cortex is congenitally small, a condition known as microcephaly (small brain). A significant cause of mental retardation, microcephaly is frequently genetic. We found one gene that causes microcephaly, ARFGEF2, that is also essential for the normal "trafficking" or transport of many proteins, including beta-catenin, through the cell.

Since the increase in size of the cortex is such a prominent part of human evolution, it is no surprise that some genes that cause microcephaly were also targets of evolutionary selection leading up to humans. ASPM, another gene for human microcephaly that we identified, has undergone remarkable changes in evolution, with the size of the encoded protein increasing dramatically from worms to flies to rodents to humans. Between humans and other primates, the protein sequence shows specific sequence alterations that appear to have been important evolutionarily.