Epilepsy, mental retardation and structural anomalies of the brain together afflict 3-5 percent of all children, yet the underlying pathogeneses for these disorders is poorly understood in most cases. Cell migration is a central component of normal central nervous system (CNS) development and disruptions in this process have been implicated in the development of these disorders. Two primary patterns of cell migration are recognized during CNS development, radial and non-radial. While the cellular and molecular bases of radial cell migration, long considered the predominant mode of cell migration, have begun to be defined, the mechanisms of guidance for non-radial cell migration remain largely unexplored. Using lineage analysis, we have defined the developmental time and location where non-radial cell migration begins in the chick forebrain. Based on these data we have developed a model to explain the cellular and molecular mechanisms of non-radial cell migration. Our model is based on the hypotheses that cell surface molecules, secreted molecules, and extracellular matrix molecules guide non-radially migrating cells. In this proposal, we intend to develop in vitro assays that will allow us to test our hypothesis and identify new molecules participating in the guidance of non-radial cell migration. We anticipate this system will provide us with a more rapid means of identifying and testing molecules essential for cell migration and therefore normal brain development. We will then be in a position to test the contribution of non-radial cell migration, and these molecules in particular, in the pathogenesis of a variety of conditions that afflict children such as epilepsy, mental retardation and structural malformations of the brain. These data will enhance our understanding of CNS development and may ultimately lead to improvements in the diagnosis, management, and prevention of neurological diseases where abnormal cell migration has a pathogenetic role.
| Nasrallah, Ilya M; McManus, Matthew F; Pancoast, Maclean M et al. (2006) Analysis of non-radial interneuron migration dynamics and its disruption in Lis1+/- mice. J Comp Neurol 496:847-58 |
| McManus, Matthew F; Golden, Jeffrey A (2005) Neuronal migration in developmental disorders. J Child Neurol 20:280-6 |
| McManus, Matthew F; Nasrallah, Ilya M; Pancoast, MacLean M et al. (2004) Lis1 is necessary for normal non-radial migration of inhibitory interneurons. Am J Pathol 165:775-84 |
| McManus, Matthew F; Nasrallah, Ilya M; Gopal, Pallavi P et al. (2004) Axon mediated interneuron migration. J Neuropathol Exp Neurol 63:932-41 |
