Molecular basis of human neurological disorders
The major area of emphasis in my laboratory is the study of the genetic and cell biological basis of human brain development. We start our studies with analysis of disorders of human development, including epileptic disorders, mental retardation, and abnormalities in brain structure. We work to identify one or more genes that is mutated in each of these conditions. The identification of such genes provides tremendous insight, because it informs us about the role of the gene in the human brain. Once a gene for a particular condition has been identified, we work with cell biological and genetic tools to identify the role of the gene in basic neurobiological processes.
We have been focusing on two major conditions that are important cause of disease in humans. The first is disordered neuronal migration. Neurons that populate the cerebral cortex are not born within the gray matter, but instead they are born along the lining of the lateral ventricle. These young neurons then migrate great distances to achieve proper positioning within the correct lamina of the developing cortex. When this is disrupted, cortical gyri and sulci are malformed and the cortex is improperly laminated. We work on the doublecortin family of genes, encoding novel microtubule-associated proteins, to understand their role in brain development. When mutated, doublecortin gives rise to human lissencephaly, consisting of a smooth brain. We are currently focused on understanding the role of this gene family in migration, in establishing cell polarity, and in organization of the microtubule cytoskeleton.
The other condition of focus in the lab is congenital ataxia, where humans are born with severe balance disturbances and malformations of the cerebellum. We work on the most common of these disorders known as Joubert syndrome where the midline of the cerebellum (known as the vermis) is completely absent. We have identified the first genes for this condition, which encode novel proteins. There is evidence to suggest that in this condition the major axonal tracts fail to form properly, suggesting that the genes also play important roles in axonal guidance. We are currently studying the molecular basis of Joubert syndrome, identifying additional Jouberin genes, and working to understand the role of these genes in brain development.
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