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.
Control of Cerebral Cortical Size
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. The increased size of the cortex is associated with the elaboration of neurons that are not seen in the smaller cortex of smaller mammals. How is the size of the cerebral cortex controlled? 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 have collaborated with others to define a number of genes that cause microcephaly, including ARFGEF2, ASPM, CDK5RAP2, CENPJ, COH1, NDE1, and PNKP. Animal studies suggest that some of these genes (including ASPM, CDK5RAP2, CENPJ, and NDE1) regulate components of the centrosome and mitotic spindle that are essential for proper cell division. Other genes, such as ARFGEF2, regulate the intracellular localization of proteins that regulate the decisions of cells to divide, or to stop dividing and differentiate.
Patterning the Human Cerebral Cortex
he cerebral cortex is divided into different regions with different functions (such as movement, language, and vision), and the size of each of these areas relates to the importance of the function. For example, humans have very large frontal lobes, which regulate speech, social interactions, and cognition. Genetic disorders of human cortical development can disrupt this mapping of the cortex in specific ways. When GPR56, a gene that encodes a new member of the family of G protein–coupled receptors, is mutated in humans, the frontal lobes are severely malformed, while other parts of the cerebral cortex are relatively preserved, suggesting that this gene is intimately involved in defining the frontal lobes.
One unique aspect of the human brain is the specialization of the right and left cerebral cortex for different functions. In most people, the left hemisphere preferentially controls speech and language and mathematical ability, whereas the right hemisphere tends to dominate spatial, artistic, and emotional functions. We have identified dozens of genes that differ in their expression between the developing language areas of the human left cerebral cortex and the corresponding regions on the right, and we are studying their effects in patterning the cerebral cortex.
Neuronal Migration to the Cortex
eurons of the cerebral cortex migrate up to thousands of times their size, from the progenitor layer deep inside the brain to the outer cortical regions where they differentiate and reside through life. Several genetic causes of mental retardation and epilepsy regulate this migration, so that affected patients end up with neurons in the wrong place in the brain. These misplaced neurons can be easily seen with magnetic resonance imaging (MRI), which noninvasively images the human brain with great precision. MRI also tells us that each gene regulates a specific task during neuronal migration. FLNA is required for neurons to start migrating; when it is lacking, many neurons never migrate. Other genes, such as DCX and LIS1, are essential in middle stages of migration; DCX seems to control neuronal shape by regulating tubulin, a component of the cellular cytoskeleton. Still other genes, such as Reelin, normally arrest neurons in the right place by inducing neurons to let go of nonneuronal cells that guide their migration, allowing these neurons to form new attachments with other neurons. Mutations in each of these genes cause very different effects on brain structure and cause distinct cognitive or other neurological problems for affected children, ranging from surprisingly mild to tragically profound.
Human Brain Evolution
We have been surprised recently to discover that some of the genes that cause developmental disorders of the human brain when severely mutated, also have undergone more subtle changes over the course of human brain evolution. For instance, ASPM, which when mutated causes microcephaly, has undergone remarkable changes in evolution, with the size of the encoded protein increasing dramatically from worms to flies to rodents to humans, and with more specific sequence alterations between nonhuman primates and humans that appear to have been important evolutionarily. This is perhaps not surprising since the large size of our brain is so characteristic of humans. AHI1, a gene that is mutated in Joubert syndrome (a human disorder characterized by mental retardation, occasional autistic symptoms, and severe defects in coordination because of abnormal patterns of nerve fiber connection), also shows dramatic evidence for "positive" evolutionary change between nonhuman primates and humans. GPR56, which regulates frontal lobe development, is either highly divergent or absent in the genome of nonmammals that lack a frontal lobe. Indeed, many disorders of children affect just those behaviors that most define us as human, such as intelligence (affected in mental retardation), complex social interactions (affected in autism and attention deficit hyperactivity disorder), and language and reading (affected in dyslexia), suggesting that other genes that cause some of these disorders when mutated may have helped define us evolutionarily as human.
In studying genetic disorders of human cortical development, we are fortunate to have extremely talented collaborators, including pediatricians, neuroradiologists, geneticists, and other neurologists, since the conditions are individually rare though collectively common. We collaborate with physicians all over the world, often in areas such as Turkey and the Middle East where the large family sizes and unique populations are more favorable for genetic analysis. In addition to our gene-mapping efforts, we try to provide diagnostic expertise for doctors and patients, since the surprising diversity of genetic disorders of human cortical development is only beginning to be appreciated.