Impaired adult neurogenesis in mice lacking the transcription factor E2F1.
ABSTRACT During nervous system development the fate of neural stem cells-whether to undergo proliferation, differentiation, or apoptosis-is controlled by various signals, such as growth factors. Here, we demonstrate that the transcription factor E2F1, which is targeted by several signaling cascades that are activated by growth factors, is involved in neurogenesis in the adult brain. When analyzing the brains of E2F1-deficient mice, we found significantly decreased stem cell and progenitor division in the proliferative zones of the lateral ventricle wall and the hippocampus. As a consequence, the production of newborn neurons in the adult olfactory bulb and dentate gyrus was decreased. Neuronal cell counts of the adult cerebellum revealed a mild but significant cerebellar atrophy, whereas neocortical neurons were unaffected, suggesting that E2F1 deficiency produces a predominantly postnatal phenotype. The results indicate an involvement of E2F1 in controlling proliferation and neuronal cell numbers in the postnatal and adult brain.
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ABSTRACT: The adult central nervous system was thought to be very limited in its regenerative potential; however, the discovery that stem cell populations produce neurons in the adult brain highlights the dynamics of a previously assumed 'static' organ. The continuous generation of new neurons in the adult brain, nevertheless, leads to the question of whether neurogenesis is counterbalanced by an accompanying cell death in the same regions. The objective of this study was to stereologically analyze neurogenesis and programmed cell death in adult brain regions with known neurogenic activity. Using bromodeoxyuridine (BrdU) to identify newborn cells we find that within a few days of BrdU-labeling the adult dentate gyrus and olfactory bulb generate high numbers of newborn neurons. More importantly, dUTP-nick end labeling (TUNEL) reveals that areas of adult neurogenesis also contain high numbers of apoptotic cells. We conclude that programmed cell death may have an important regulatory function by eliminating supernumerous cells from neurogenic regions and may thus contribute to a self-renewal mechanism in the adult mammalian brain.Neuroscience Letters 10/2000; 291(1):17-20. · 2.03 Impact Factor
Article: Oncogenic capacity of the E2F1 gene.[show abstract] [hide abstract]
ABSTRACT: Previous experiments have identified the E2F transcription factor as a potential downstream target for the action of cellular regulatory activities, such as the Rb tumor suppressor protein, that control cell growth and that, when altered, contribute to the development of human tumors. In light of these findings, we have assayed the ability of the E2F1 and DP1 genes, which encode heterodimeric partners that together create E2F activity, to act in an oncogenic fashion. We find that E2F1, particularly in combination with the DP1 product, cooperates with an activated ras oncogene to induce the formation of morphologically transformed foci in primary rat embryo fibroblast cultures. In addition, an E2F1 chimeric protein, in which sequences involved in Rb binding have been replaced with the herpesvirus VP16 activation domain, exhibits increased transformation activity. Cells transfected with E2F1 and DP1 or the E2F1-VP16 chimera form colonies in soft agar and induce tumor formation in nude mice. We conclude that deregulated E2F1 expression and function can have oncogenic consequences.Proceedings of the National Academy of Sciences 01/1995; 91(26):12823-7. · 9.74 Impact Factor
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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.  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. (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.  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.Developmental Dynamics 11/1998; 213(2):220-7. · 2.59 Impact Factor