Oct-3/4 repression accelerates differentiation of neural progenitor cells in vitro and in vivo

Okuda, Tomohiro; Tagawa, Kazuhiko; Qi, Mei-Ling; Hoshio, Masataka; Ueda, Hiroko; Kawano, Hitoshi; Kanazawa, Ichiro; Muramatsu, Masami; Okazawa, Hitoshi

doi:10.1016/j.molbrainres.2004.08.021

Cited by 51 publications

(39 citation statements)

References 31 publications

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“…We found that several individual motifs were significantly enriched in 43 human tissues (Supplemental Table S1). For example, we observed a strong association among NRF1, POU2F1, MEF2A, and CREB1, transcription factors known to play key roles in brain and neural development (Ilia et al 2003;Okuda et al 2004;Chang et al 2005;Shalizi and Bonni 2005;Riccio et al 2006) in candidate regulatory elements from loci highly expressed in human fetal brain (Supplemental Table S1A). However, as described in further detail below, no single TF by itself was sufficient to predict where a candidate enhancer will drive gene expression.…”

Section: Predicting Candidate Regulatory Elements For Tissue-specificmentioning

confidence: 99%

Predicting tissue-specific enhancers in the human genome

Pennacchio¹,

Loots²,

Nóbrega³

et al. 2007

Genome Res.

127

131

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Determining how transcriptional regulatory signals are encoded in vertebrate genomes is essential for understanding the origins of multicellular complexity; yet the genetic code of vertebrate gene regulation remains poorly understood. In an attempt to elucidate this code, we synergistically combined genome-wide gene-expression profiling, vertebrate genome comparisons, and transcription factor binding-site analysis to define sequence signatures characteristic of candidate tissue-specific enhancers in the human genome. We applied this strategy to microarray-based gene expression profiles from 79 human tissues and identified 7187 candidate enhancers that defined their flanking gene expression, the majority of which were located outside of known promoters. We cross-validated this method for its ability to de novo predict tissue-specific gene expression and confirmed its reliability in 57 of the 79 available human tissues, with an average precision in enhancer recognition ranging from 32% to 63% and a sensitivity of 47%. We used the sequence signatures identified by this approach to successfully assign tissue-specific predictions to ∼328,000 human-mouse conserved noncoding elements in the human genome. By overlapping these genome-wide predictions with a data set of enhancers validated in vivo, in transgenic mice, we were able to confirm our results with a 28% sensitivity and 50% precision. These results indicate the power of combining complementary genomic data sets as an initial computational foray into a global view of tissue-specific gene regulation in vertebrates.

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Section: Predicting Candidate Regulatory Elements For Tissue-specificmentioning

confidence: 99%

Predicting tissue-specific enhancers in the human genome

Pennacchio¹,

Loots²,

Nóbrega³

et al. 2007

Genome Res.

127

131

View full text Add to dashboard Cite

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“…On the contrary, the culture of retinal cells was characterized by enhanced Oct4 expression. In previous studies, expression of this factor was detected in cultured rat brain cells, but not in native rat brain [4,11].…”

Section: Resultsmentioning

confidence: 99%

“…The study was performed on brain neocortex and retina isolated from nonviable human fetuses on gestation weeks 8,9,11,12,[18][19][20], and 24-26 obtained during medical abortion. The biomaterial was obtained from licensed clinics of the Ministry of Health of the Russian Federation working within the limits of Federal law on health protection and in accordance with the approved list of medical indications.…”

Section: Methodsmentioning

confidence: 99%

Comparative Analysis of the Expression of Neural Stem Cell-Associated Genes during Neocortex and Retina Development in Human

et al. 2013

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We compared the expression of Sox2, Oct4, Nanog, Pax6, Prox1 genes associated with plasticity of neural stem and progenitor cells during human neocortex and retina development and in cell cultures. At the analyzed stages of neurogenesis, Pax6 gene is expressed in the neocortex and retina at constant levels, the expression is by one order of magnitude higher in the retina. The dynamics of Sox2 and Pax6 expression in the neocortex was similar. The expression of Oct4 and Nanog genes during neurogenesis in the neocortex and human fetal retina reflects the existence of a high-plasticity cell pool. The dynamics of βIII-tubulin expression indicates that the retina develops more rapidly than the neocortex. Our experiments showed that genetically determined cell potencies typical of native cells are realized in primary cultures without specific stimulation.

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“…Therefore, a finely tuned control of Oct-3/4 expression is crucial to maintain undifferentiated status of stem cells. There have been several contrasting reports regarding the expression of Oct-3/4 in neural stem cells (29 -31), although several studies unequivocally demonstrate the role of Oct-3/4 in maintaining their pluripotency (17,19,20,32,33). It is widely agreed that Oct-3/4 is essential to maintain the stemness, and its ectopic expression in adult neural stem cells could generate induced pluripotent stem cells (19,20,34).…”

Section: Discussionmentioning

confidence: 99%

“…In this context, our studies were driven by the fact that Oct-3/4 is a hypoxia-driven factor (16), and it has also been shown to be expressed in neural stem cells albeit to a lower degree (17,18). Hence, our next step was to investigate if TLX could regulate the expression of Oct-3/4.…”

Section: Hypoxia-mediated Tlx Expression Is Independent Of Fgf-mentioning

confidence: 99%

Nuclear Orphan Receptor TLX Induces Oct-3/4 for the Survival and Maintenance of Adult Hippocampal Progenitors upon Hypoxia

Chavali

Saini

Matsumoto

et al. 2011

Journal of Biological Chemistry

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Hypoxia promotes neural stem cell proliferation, the mechanism of which is poorly understood. Here, we have identified the nuclear orphan receptor TLX as a mediator for proliferation and pluripotency of neural progenitors upon hypoxia. We found an enhanced early protein expression of TLX under hypoxia potentiating sustained proliferation of neural progenitors. Moreover, TLX induction upon hypoxia in differentiating conditions leads to proliferation and a stem cell-like phenotype, along with coexpression of neural stem cell markers. Following hypoxia, TLX is recruited to the Oct-3/4 proximal promoter, augmenting the gene transcription and promoting progenitor proliferation and pluripotency. Knockdown of Oct-3/4 significantly reduced TLX-mediated proliferation, highlighting their interdependence in regulating the progenitor pool. Additionally, TLX synergizes with basic FGF to sustain cell viability upon hypoxia, since the knockdown of TLX along with the withdrawal of growth factor results in cell death. This can be attributed to the activation of Akt signaling pathway by TLX, the depletion of which results in reduced proliferation of progenitor cells. Cumulatively, the data presented here demonstrate a new role for TLX in neural stem cell proliferation and pluripotency upon hypoxia.The adult brain retains a reservoir of stem progenitor cells in the hippocampal "neurogenic zone" capable of proliferative activity throughout life (1). These undifferentiated precursors that retain the ability to proliferate and self-renew can give rise to both neuronal and glial lineages (2). Recent studies have emphasized the role of hypoxia in maintaining pluripotency and increased proliferation of neural stem cells (3-5).However, the molecular mechanisms underlying the increased proliferation and pluripotency of neural stem cells are yet unexplored. TLX (NR2E1), an orphan nuclear receptor expressed in vertebrate forebrains (6), is an essential regulator of adult neural stem cell self-renewal (7). TLX maintains neural stem cells in an undifferentiated and self-renewable state by complexing with histone deacetylases to repress TLX downstream target genes, such as p21 and Pten, promoting cellular proliferation (8). Furthermore, TLX is expressed in the subventricular neural stem cells in embryonic brains and plays an important role in neural development by regulating cell cycle progression of neural stem cells (9 -11). Also, TLXpositive neural stem cells play an important role in spatial learning and memory in adult brains (12).This study aimed to investigate the role of TLX in promoting neural progenitor population under differentiating conditions, considering the fact that TLX acts as a hypoxic sensor in retinal astrocytes (13), and hypoxia promotes proliferation/ dedifferentiation of progenitor cells. Our results demonstrate that TLX is responsive to hypoxia in both differentiating and proliferating conditions. The knockdown of TLX attenuates hypoxia-mediated progenitor proliferation and induces differentiation. Further investigatio...

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Oct-3/4 repression accelerates differentiation of neural progenitor cells in vitro and in vivo

Cited by 51 publications

References 31 publications

Predicting tissue-specific enhancers in the human genome

Predicting tissue-specific enhancers in the human genome

Comparative Analysis of the Expression of Neural Stem Cell-Associated Genes during Neocortex and Retina Development in Human

Nuclear Orphan Receptor TLX Induces Oct-3/4 for the Survival and Maintenance of Adult Hippocampal Progenitors upon Hypoxia

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