| Neurons have been considered to be terminally postmitotic once they initiate differentiation. However, a population of progenitor cells in the neonatal anterior subventricular zone (SVZa) of the forebrain continues to divide despite expressing properties of differentiated neurons. SVZa progenitor cells undergo division as they migrate to the olfactory bulb along the rostral migratory stream (RMS). We hypothesized that the proliferative behavior of SVZa neuronal progenitor cells can be explained by the manner in which they regulate their cell cycle. We examined the cyclin dependent kinase inhibitors (CKIs) to determine whether their expression leads to cell cycle exit of SVZa progenitor cells. CKIs, p19Ink4d and p27Kip1, exhibit an anterior high-posteriorlow gradient of expression along the RMS of neonatal rat pups. Even though, p19Ink4d and p27 Kip1 immunoreactivity overlaps, they are not coexpressed concurrently. Furthermore, the proliferative behavior of SVZa progenitor cells in p19 Ink4d, p27Kip1 and p19 Ink4d/p27Kip1 knock out mice reveal that p19Ink4d and p27Kip1 do not cooperatively control the proliferation of SVZa progenitor cells. To determine whether Bone Morphogenetic Proteins (BMPs) regulate the cell cycle of SVZa neuronal progenitor cells, we injected a retrovirus encoding either the wild type (wt) or dominant-negative (dn) BMP receptor-la (BMPR-Ia) into the SVZa, to augment or block BMP signaling, respectively. The cells in the SVZa encoding the wt BMPR-Ia ectopically express p19Ink4d, where as SVZa-derived cells encoding the dn BMPR-Ia along the RMS do not express p19Ink4d. These findings indicate that BMPs act as an extrinsic signal regulating the proliferation of SVZa progenitor cells. Our observation that cells in the RMS do not become permanently postmitotic following their expression of the cell cycle inhibitor p19 Ink4d suggests that SVZa-derived cells in the RMS cyclically downregulate p19Ink4d, undergo division and then re-express p19Ink4d . In order to evaluate whether SVZa progenitor cells undergo rounds of differentiation-dedifferentiation, we analyzed the proliferative behavior of SVZa cells in vitro using time-lapse videomicroscopy. We observed that cultured SVZa neuronal progenitor cells repeatedly retract their processes, then divide and the progeny subsequently re-extend processes. Collectively, our data provide a mechanism for how SVZa progenitor cells with a neuronal phenotype retain the ability for cell division. |
