Cells originating from the anterior-most portion of the subventricular zone (SVZa) are destined to become interneurons of the olfactory bulb. These SVZa-derived cells migrate to the olfactory bulb along a very restricted pathway known as the rostral migratory stream (RMS). Although the guidance mechanisms used by SVZa-derived cells as they traverse the RMS are poorly understood, cues directing the migration and process outgrowth of other neuronal cell types may be involved. Specific factors that will be examined in this study are tissue plasminogen activator (tPA), a serine protease that facilitates the migration of cerebellar granule cells and is expressed by cells in the mouse SVZa and RMS, and the semaphorins, which are a family of predominantly chemorepulsive signaling molecules that guide the migration and process outgrowth of many CNS neuronal cell types. In addition, this study will determine whether the border of the RMS produces a chemorepellent that serves to restrict migrating SVZa-derived cells to their pathway. To investigate the importance of these factors, SVZa-derived cell migration in vivo, in explant cultures, and in slice cultures will be analyzed in the presence and absence of biochemical inhibitors, function-blocking antibodies, and a dominant-negative construct delivered by a retroviral vector. These studies will lead to a better understanding of the guidance mechanisms of neuronal migration and may give insight into the processes underlying developmental disorders of neuronal migration.
