Upregulation of E2F1 in cerebellar neuroprogenitor cells and cell cycle arrest during postnatal brain development

Abstract

In the developing cerebellum, proliferation of granular neuroprogenitor (GNP) cells lasts until the early postnatal stages when terminal maturation of the cerebellar cortex occurs. GNPs are considered cell targets for neoplastic transformation, and disturbances in cerebellar GNP cell proliferation may contribute to the development of pediatric medulloblastoma. At the molecular level, proliferation of GNPs is regulated through an orchestrated action of the SHH, NOTCH, and WNT pathways, but the underlying mechanisms still need to be dissected. Here, we report that expression of the E2F1 transcription factor in rat GNPs is inversely correlated with cell proliferation rate during postnatal development, as opposed to its traditional SHH-dependent induction of cell cycle. Proliferation of GNPs peaked at postnatal day 3 (P3), with a subsequent continuing decrease in proliferation rates occurring until P12. Such gradual decline in proliferating neuroprogenitors paralleled the extent of cerebellum maturation confirmed by histological analysis with cresyl violet staining and temporal expression profiling of SHH, NOTCH2, and WNT4 genes. A time course analysis of E2F1 expression in GNPs revealed significantly increased levels at P12, correlating with decreased cell proliferation. Expression of the cell cycle inhibitor p18 ( Ink4c ), a target of E2F1, was also significantly higher at P12. Conversely, increased E2F1 expression did not correlate with either SMAC/DIABLO and BCL2 expression profiles or apoptosis of cerebellar cells. Altogether, these results suggest that E2F1 may also be involved in the inhibition of GNP proliferation during rat postnatal development despite its conventional mitogenic effects.

Dynamic Changes of CD44 Expression from Progenitors to Subpopulations of Astrocytes and Neurons in Developing Cerebellum

“…The reduction of neural stem/progenitor cell number in postnatal cerebellum (Fig. 5B, 5E and 5H) was supported by previous report, which revealed dividing cells and nestin-positive cells decreased in rat postnatal cerebellum during development [33].…”

An essential role for p38 MAPK in cerebellar granule neuron precursor proliferation

“…Activation of Smo ultimately leads to transcriptional activity of the Gli transcription factors, which themselves regulate a gene expression program resulting in proliferation and survival [22,23,25,54]. In addition to the Gli factors, Shh activity also induces expression of oncogenes N-Myc, E2F1, YAP, and the microRNA miR 17/92, which are required for CGNP proliferation [4,16,28,42,56]. An additional feed-forward loop wherein N-Myc up-regulates eIF4E to ultimately inhibit S6 Kinase, stabilizing IRS1 also drives N-Myc-dependent CGNP proliferation [36].…”

Principal component analysis-based unsupervised feature extraction applied to single-cell gene expression analysis1

“…Additionally, CEBPD and CREB were reported to be related to brain disease [35,36]. E2F1 was reported to be related to postnatal brain development [37] while functional EGR1 was found in the embryonic rat brain [38]. PML and SIN3A were also reported to be involved in brain development [39] [40].…”