Impaired Adult Neurogenesis in Mice Lacking the Transcription Factor E2F1

Department of Neurology, University of Regensburg, D-93053 Regensburg, Germany.
Molecular and Cellular Neuroscience (Impact Factor: 3.84). 11/2002; 21(2):312-23. DOI: 10.1006/mcne.2002.1176
Source: PubMed


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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    • "Notably, other genes not in our combined human and mouse candidate list, including Cdon, Dbi and Pcnt, also exhibit potential effects during neural development (Zhang et al., 2006; Oh et al., 2009; Buchman et al., 2010; Endoh-Yamagami et al., 2010; Alfonso et al., 2012). Loss of E2f5 does not perturb cell proliferation in the VZ during early development in mice (Lindeman et al., 1998), which might be due to the compensating effect of other E2F transcription factors (e.g., E2f1) (Yoshikawa, 2000; Cooper-Kuhn et al., 2002). Hmgn2 and Ssrp1 are both chromatin binding proteins that are novel potential regulators of neocortical development implicated by our examination of a publically available dataset. "
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    ABSTRACT: Neurons of the mammalian neocortex are produced by proliferating cells located in the ventricular zone (VZ) lining the lateral ventricles. This is a complex and sequential process, requiring precise control of cell cycle progression, fate commitment and differentiation. We have analyzed publicly available databases from mouse and human to identify candidate genes that are potentially involved in regulating early neocortical development and neurogenesis. We used a mouse in situ hybridization dataset (The Allen Institute for Brain Science) to identify 13 genes (Cdon, Celsr1, Dbi, E2f5, Eomes, Hmgn2, Neurog2, Notch1, Pcnt, Sox3, Ssrp1, Tead2, Tgif2) with high correlation of expression in the proliferating cells of the VZ of the neocortex at early stages of development (E15.5). We generated a similar human brain network using microarray and RNA-seq data (BrainSpan Atlas) and identified 407 genes with high expression in the developing human VZ and subventricular zone (SVZ) at 8-9 post-conception weeks. Seven of the human genes were also present in the mouse VZ network. The human and mouse networks were extended using available genetic and proteomic datasets through GeneMANIA. A gene ontology search of the mouse and human networks indicated that many of the genes are involved in the cell cycle, DNA replication, mitosis and transcriptional regulation. The reported involvement of Cdon, Celsr1, Dbi, Eomes, Neurog2, Notch1, Pcnt, Sox3, Tead2 and Tgif2 in neural development or diseases resulting from the disruption of neurogenesis validates these candidate genes. Taken together, our knowledge-based discovery method has validated the involvement of many genes already known to be involved in neocortical development and extended the potential number of genes by 100's, many of which are involved in functions related to cell proliferation but others of which are potential candidates for involvement in the regulation of neocortical development.
    Frontiers in Neuroscience 08/2014; 8(8). DOI:10.3389/fnins.2014.00257 · 3.66 Impact Factor
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    • "In the context of adult neurogenesis, E2F1 was shown to be important for cell proliferation and differentiation. Using a single BrdU injection paradigm, 2h before sacrifice, Cooper-Kuhn et al. [72] showed that E2F1-deficient mice have decreased cell proliferation and diminished neurogenesis, both in the hippocampal DG and the SVZ. These authors also described a decrease of about 60-70 % in apoptotic cells, in the hippocampal neurogenic niche of E2F1-deficient mice compared to wild-type (WT), further corroborating the role of this gene in regulating cell death in the context of adult neurogenesis [72]. "
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    ABSTRACT: Since adult neurogenesis became a widely accepted phenomenon, much effort has been put in trying to understand the mechanisms involved in its regulation. In addition, the pathophysiology of several neuropsychiatric disorders, such as depression, has been associated with imbalances in adult hippocampal neurogenesis. These imbalances may ultimately reflect alterations at the cell cycle level, as a common mechanism through which intrinsic and extrinsic stimuli interact with the neurogenic niche properties. Thus, the comprehension of these regulatory mechanisms has become of major importance to disclose novel therapeutic targets. In this review, we first present a comprehensive view on the cell cycle components and mechanisms that were identified in the context of the homeostatic adult hippocampal neurogenic niche. Then, we focus on recent work regarding the cell cycle changes and signaling pathways that are responsible for the neurogenesis imbalances observed in neuropathological conditions, with a particular emphasis on depression.
    Molecular Neurobiology 03/2013; 48(1). DOI:10.1007/s12035-013-8422-x · 5.14 Impact Factor
    • "Furthermore, transgenic mice over-expressing E2F1 show inhibited chondrocyte differentiation, which is reflected by delayed bone formation (52). On the other hand, loss of E2F1 in transgenic mice led to decreased neurogenic activity (53). "
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    ABSTRACT: Stem cell fate decisions are controlled by a molecular network in which transcription factors and miRNAs are of key importance. To systemically investigate their impact on neural stem cell (NSC) maintenance and neuronal commitment, we performed a high-throughput mRNA and miRNA profiling and isolated functional interaction networks of involved mechanisms. Thereby, we identified an E2F1-miRNA feedback loop as important regulator of NSC fate decisions. Although E2F1 supports NSC proliferation and represses transcription of miRNAs from the miR-17∼92 and miR-106a∼363 clusters, these miRNAs are transiently up-regulated at early stages of neuronal differentiation. In these early committed cells, increased miRNAs expression levels directly repress E2F1 mRNA levels and inhibit cellular proliferation. In mice, we demonstrated that these miRNAs are expressed in the neurogenic areas and that E2F1 inhibition represses NSC proliferation. The here presented data suggest a novel interaction mechanism between E2F1 and miR-17∼92 / miR-106a∼363 miRNAs in controlling NSC proliferation and neuronal differentiation.
    Nucleic Acids Research 02/2013; 41(6). DOI:10.1093/nar/gkt070 · 9.11 Impact Factor
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