Christopher A. Walsh, MD, PhD
Harvard Medical School
Howard Hughes Medical Institute
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 stem cells and 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. 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.
Genes that are mutated in human microcephaly encode proteins that regulate several key functions in neural stem cells. Some microcephaly genes encode components of the mitotic spindle, and others encode regulators of DNA repair. Other microcephaly genes appear to regulate protein trafficking in stem cells, since the pattern of protein distribution in stem cells seems critical for controlling proliferation. Since the increase in size of the cortex is such a prominent part of human evolution, it is perhaps no surprise that some genes that cause microcephaly were targets of evolutionary selection leading up to humans.
In addition to using human genetics to identify regulators of neural stem cells, we are also using mother methods to understand neural stem cells. In one recent study, we identified dozens of secreted factors present in the niche of cerebral cortical progenitor cells, and found that the cerebrospinal fluid that surrounds the developing brain also contains factors that regulate stem cell divisions in the brain.
Christopher Walsh is Bullard Professor of Pediatrics and Neurology at Harvard Medical School, Chief of the Division of Genetics at Boston Children's Hospital, and an Investigator of the Howard Hughes Medical Institute. He completed his M.D. and Ph.D. degrees at the University of Chicago. After a neurology residency and chief residency at Massachusetts General Hospital, he completed a research fellowship in genetics at Harvard Medical School. Dr. Walsh has studied patterns of neural stem cell division, cell fate choices, and cell migrations in the developing cerebral cortex, and has pioneered the analysis of human genetic diseases that disrupt the cerebral cortex. Among his awards are a Jacob Javits Neuroscience Investigator Award from the NINDS, the Dreifuss-Penry Award from the American Academy of Neurology, the Derek Denny-Brown Award from the American Neurological Association, the Wilder Penfield Award of the Middle Eastern Medical Assembly, and the Research Award from the American Epilepsy Society.