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Dynamic expression of notch signaling genes in neural stem/progenitor cells.

Shimojo H, Ohtsuka T, Kageyama R - Front Neurosci (2011)

Bottom Line: In neural stem/progenitor cells, expression of the Notch effector Hes1, a transcriptional repressor, oscillates with a period of 2-3 h by negative feedback, and Hes1 oscillations induce the oscillatory expression of the proneural gene Neurogenin2 (Ngn2) and the Notch ligand gene Delta-like1 (Dll1).Thus, Ngn2 leads to the maintenance of neural stem/progenitor cells by inducing Dll1 oscillation when its expression oscillates but to neuronal differentiation when its expression is sustained.These results indicate that the different dynamics of Hes1 and Ngn2 lead to different outcomes.

View Article: PubMed Central - PubMed

Affiliation: Institute for Virus Research, Kyoto University Kyoto, Japan.

ABSTRACT
In neural stem/progenitor cells, expression of the Notch effector Hes1, a transcriptional repressor, oscillates with a period of 2-3 h by negative feedback, and Hes1 oscillations induce the oscillatory expression of the proneural gene Neurogenin2 (Ngn2) and the Notch ligand gene Delta-like1 (Dll1). Dll1 oscillation leads to the mutual activation of Notch signaling between neighboring cells, thereby maintaining a group of cells in the undifferentiated state. Not all cells express Hes1 in an oscillatory manner: cells in boundary regions such as the isthmus express Hes1 in a sustained manner, and these cells are rather dormant with regard to proliferation and differentiation. Thus, Hes1 allows cell proliferation and differentiation when its expression oscillates but induces dormancy when its expression is sustained. After Hes1 expression is repressed, Ngn2 is expressed in a sustained manner, promoting neuronal differentiation. Thus, Ngn2 leads to the maintenance of neural stem/progenitor cells by inducing Dll1 oscillation when its expression oscillates but to neuronal differentiation when its expression is sustained. These results indicate that the different dynamics of Hes1 and Ngn2 lead to different outcomes.

No MeSH data available.


Oscillatory expression of Hes1. Hes1 expression oscillates with a period of ∼2 h in many cell types such as neural stem/progenitor cells and fibroblasts. Hes1 represses its own expression by directly binding to its promoter. This negative feedback leads to the disappearance of Hes1 mRNA and protein, because they are extremely unstable, allowing the next round of its expression. In this way, Hes1 autonomously starts an oscillatory expression pattern.
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Figure 3: Oscillatory expression of Hes1. Hes1 expression oscillates with a period of ∼2 h in many cell types such as neural stem/progenitor cells and fibroblasts. Hes1 represses its own expression by directly binding to its promoter. This negative feedback leads to the disappearance of Hes1 mRNA and protein, because they are extremely unstable, allowing the next round of its expression. In this way, Hes1 autonomously starts an oscillatory expression pattern.

Mentions: Time-lapse imaging analysis revealed that Hes1 expression oscillates in neural stem/progenitor cells (Masamizu et al., 2006; Shimojo et al., 2008). Hes1 represses its own expression by directly binding to its promoter. This negative feedback leads to the disappearance of Hes1 mRNA and protein because they are extremely unstable, but the disappearance of Hes1 protein allows the next round of its expression. In this way, Hes1 expression oscillates with a period of ∼2–3 h in neural stem/progenitor cells (Figure 3; Hirata et al., 2002). Hes1 protein expression exhibits an inverse correlation with Ngn2 protein and Dll1 mRNA expression in neural stem/progenitor cells, suggesting that Hes1 oscillation induces the oscillatory expression of Ngn2 and Dll1 by periodic repression (Shimojo et al., 2008). Indeed, time-lapse imaging analysis revealed that Ngn2 and Dll1 expression oscillates in neural stem/progenitor cells, where Hes1 expression oscillates, whereas their expression is sustained in differentiating neurons, where Hes1 expression is repressed (Figure 4; Shimojo et al., 2008). It is likely that Ngn2 cannot induce neuronal differentiation when its expression oscillates, probably because many downstream genes respond rather slowly to Ngn2 expression. It seems that Ngn2 induces neuronal differentiation only when its expression becomes sustained, and when its expression oscillates, only quickly responding genes such as Dll1 are selectively induced. Dll1 oscillations may lead to the mutual activation of Notch signaling and the maintenance of neural stem/progenitor cells. Thus, depending on its expression dynamics, Ngn2 may lead to two opposite outcomes: when its expression oscillates, Ngn2 induces the maintenance of neural stem/progenitor cells, but when its expression is sustained, Ngn2 induces neuronal differentiation.


Dynamic expression of notch signaling genes in neural stem/progenitor cells.

Shimojo H, Ohtsuka T, Kageyama R - Front Neurosci (2011)

Oscillatory expression of Hes1. Hes1 expression oscillates with a period of ∼2 h in many cell types such as neural stem/progenitor cells and fibroblasts. Hes1 represses its own expression by directly binding to its promoter. This negative feedback leads to the disappearance of Hes1 mRNA and protein, because they are extremely unstable, allowing the next round of its expression. In this way, Hes1 autonomously starts an oscillatory expression pattern.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3116140&req=5

Figure 3: Oscillatory expression of Hes1. Hes1 expression oscillates with a period of ∼2 h in many cell types such as neural stem/progenitor cells and fibroblasts. Hes1 represses its own expression by directly binding to its promoter. This negative feedback leads to the disappearance of Hes1 mRNA and protein, because they are extremely unstable, allowing the next round of its expression. In this way, Hes1 autonomously starts an oscillatory expression pattern.
Mentions: Time-lapse imaging analysis revealed that Hes1 expression oscillates in neural stem/progenitor cells (Masamizu et al., 2006; Shimojo et al., 2008). Hes1 represses its own expression by directly binding to its promoter. This negative feedback leads to the disappearance of Hes1 mRNA and protein because they are extremely unstable, but the disappearance of Hes1 protein allows the next round of its expression. In this way, Hes1 expression oscillates with a period of ∼2–3 h in neural stem/progenitor cells (Figure 3; Hirata et al., 2002). Hes1 protein expression exhibits an inverse correlation with Ngn2 protein and Dll1 mRNA expression in neural stem/progenitor cells, suggesting that Hes1 oscillation induces the oscillatory expression of Ngn2 and Dll1 by periodic repression (Shimojo et al., 2008). Indeed, time-lapse imaging analysis revealed that Ngn2 and Dll1 expression oscillates in neural stem/progenitor cells, where Hes1 expression oscillates, whereas their expression is sustained in differentiating neurons, where Hes1 expression is repressed (Figure 4; Shimojo et al., 2008). It is likely that Ngn2 cannot induce neuronal differentiation when its expression oscillates, probably because many downstream genes respond rather slowly to Ngn2 expression. It seems that Ngn2 induces neuronal differentiation only when its expression becomes sustained, and when its expression oscillates, only quickly responding genes such as Dll1 are selectively induced. Dll1 oscillations may lead to the mutual activation of Notch signaling and the maintenance of neural stem/progenitor cells. Thus, depending on its expression dynamics, Ngn2 may lead to two opposite outcomes: when its expression oscillates, Ngn2 induces the maintenance of neural stem/progenitor cells, but when its expression is sustained, Ngn2 induces neuronal differentiation.

Bottom Line: In neural stem/progenitor cells, expression of the Notch effector Hes1, a transcriptional repressor, oscillates with a period of 2-3 h by negative feedback, and Hes1 oscillations induce the oscillatory expression of the proneural gene Neurogenin2 (Ngn2) and the Notch ligand gene Delta-like1 (Dll1).Thus, Ngn2 leads to the maintenance of neural stem/progenitor cells by inducing Dll1 oscillation when its expression oscillates but to neuronal differentiation when its expression is sustained.These results indicate that the different dynamics of Hes1 and Ngn2 lead to different outcomes.

View Article: PubMed Central - PubMed

Affiliation: Institute for Virus Research, Kyoto University Kyoto, Japan.

ABSTRACT
In neural stem/progenitor cells, expression of the Notch effector Hes1, a transcriptional repressor, oscillates with a period of 2-3 h by negative feedback, and Hes1 oscillations induce the oscillatory expression of the proneural gene Neurogenin2 (Ngn2) and the Notch ligand gene Delta-like1 (Dll1). Dll1 oscillation leads to the mutual activation of Notch signaling between neighboring cells, thereby maintaining a group of cells in the undifferentiated state. Not all cells express Hes1 in an oscillatory manner: cells in boundary regions such as the isthmus express Hes1 in a sustained manner, and these cells are rather dormant with regard to proliferation and differentiation. Thus, Hes1 allows cell proliferation and differentiation when its expression oscillates but induces dormancy when its expression is sustained. After Hes1 expression is repressed, Ngn2 is expressed in a sustained manner, promoting neuronal differentiation. Thus, Ngn2 leads to the maintenance of neural stem/progenitor cells by inducing Dll1 oscillation when its expression oscillates but to neuronal differentiation when its expression is sustained. These results indicate that the different dynamics of Hes1 and Ngn2 lead to different outcomes.

No MeSH data available.