Cell cycle length of olfactory bulb neuronal progenitors in the rostral migratory stream

Abstract

The anterior portion of the neonatal telencephalic subventricular zone (SVZa) contains proliferating cells that generate an immense number of neurons destined to become the granule and periglomerular cells of the olfactory bulb. In contrast to other immature neurons in the central nervous system, cells arising in the SVZa maintain the ability to divide as they traverse the rostral migratory stream to their final destinations despite expressing an antigenic marker of differentiated neurons (Menezes et al. [1995] Molec. Cell. Neurosci. 6:496-508). Because of their considerable proliferative capacities and unusual mitotic behavior, we decided to determine the cell cycle length of proliferating cells within the SVZa and within the migratory pathway used by SVZa-derived cells. Following the methodology of Nowakowski et al. [1989](J. Neurocytol. 18:311-318), postnatal day 2 rat pups were exposed to 5'-bromo-2'deoxyuridine (BrdU) for increasing periods of time before perfusion. By plotting the percentage of nuclei undergoing DNA synthesis in the SVZa at each time versus the BrdU labeling interval, we determined that approximately 15% of the SVZa population is actively dividing and that these cells have a cycle length of approximately 14 hr, significantly less than the 18.6 hr determined to be the cycle length of dividing cells in more posterior, glia-generating regions of the subventricular zone (Thomaidou et al. [1997] J. Neurosci. 17:1075-1085). The cycle length of cells dividing in the mid portion of the rostral migratory stream, however, is considerably longer: 17.3 hr. This may reflect the need for these cells to coordinate the processes of migration and division. Our studies also suggest that there may be regional differences in the types of descendants produced by the proliferating cells. Retroviral lineage tracing studies showed that those cells that divide within the rostral migratory stream, like proliferating cells within the SVZa, make cells destined for the olfactory bulb. Unlike the progenitors that divide within the SVZa and generate more granule cells than periglomerular cells, the proliferating cells within the migratory pathway generate more periglomerular cells than granule cells. Collectively the proliferating cells of the SVZa and migratory pathway produce a large number of olfactory bulb interneurons. Our work suggests that this may be achieved in part by the relatively rapid divisions of progenitor cells within the SVZa and in part by the ongoing division of migrating cells en route to the olfactory bulb.