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Review
. 2020 Jan;62(1):59-66.
doi: 10.1111/dgd.12626. Epub 2019 Sep 6.

Regulation of active and quiescent somatic stem cells by Notch signaling

Risa Sueda  1   2 , Ryoichiro Kageyama  1   2   3   4
Affiliations
Review

Regulation of active and quiescent somatic stem cells by Notch signaling

Risa Sueda et al. Dev Growth Differ. 2020 Jan.

Abstract

Somatic stem/progenitor cells actively proliferate and give rise to different types of mature cells (active state) in embryonic tissues while they are mostly dormant (quiescent state) in many adult tissues. Notch signaling is known to regulate both active and quiescent states of somatic stem cells, but how it regulates these different states is unknown. Recent studies revealed that the Notch effector Hes1 is expressed differently during the active and quiescent states during neurogenesis and myogenesis: high in the quiescent state and oscillatory in the active state. When the Hes1 expression level is high, both Ascl1 and MyoD expression are continuously suppressed. By contrast, when Hes1 expression oscillates, it periodically represses expression of the neurogenic factor Ascl1 and the myogenic factor MyoD, thereby driving Ascl1 and MyoD oscillations. High levels of Hes1 and the resultant Ascl1 suppression promote the quiescent state of neural stem cells, while Hes1 oscillation-dependent Ascl1 oscillations regulate their active state. Similarly, in satellite cells of muscles, known adult muscle stem cells, high levels of Hes1 and the resultant MyoD suppression seem to promote their quiescent state, while Hes1 oscillation-dependent MyoD oscillations activate their proliferation and differentiation. Therefore, the expression dynamics of Hes1 is a key regulatory mechanism of generating and maintaining active/quiescent stem cell states.

Keywords: Hes1; Notch signaling; active stem cell; oscillatory expression; quiescent stem cell.

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Figures

Figure 1
Figure 1
Lateral inhibition of differentiation via Notch signaling. A differentiating cell expresses Notch ligands such as Delta‐like1 (Dll1), which activate Notch signaling in a neighboring cell. The transmembrane protein Notch is then processed in the neighboring cell, releasing the Notch intracellular domain (NICD), which transits to the nucleus, forms a complex with the Notch signaling mediator Rbpj and the co‐activator Mastermind‐like (Maml), and induces transcriptional repressors such as Hes1 and Hes5. Hes1 and Hes5 inhibit cell differentiation and maintain a somatic stem cell by antagonizing cell fate determination factors such as the neurogenic factors Ascl1 and Neurog2
Figure 2
Figure 2
Neurogenesis in the embryonic and adult brain. (a) Differentiation of neural stem/progenitor cells in the embryonic cortex. Neuroepithelial cells initially undergo repeated self‐renewal by symmetric division. As development proceeds, neuroepithelial cells elongate to become radial glial cells, which have cell bodies in the inner region (the ventricular zone, VZ) of the neural tube and long processes (radial fibers) that reach the outer surface. Radial glial cells give rise to neurons and/or intermediate progenitors. Each intermediate progenitor migrates into the subventricular zone (SVZ) and produces neurons. Neurons migrate outward to form the cortical plate (CP). Some radial glial cells detach from the inner (apical) surface, form a new layer called the outer SVZ (OSVZ), and undergo asymmetric cell divisions, producing more neurons. After producing neurons, radial glial cells differentiate into glia (oligodendrocytes and astrocytes). Both neuroepithelial cells and radial glial cells are considered embryonic neural stem/progenitor cells. (b) Neurogenesis in the subgranular zone (SGZ) of the hippocampal dentate gyrus of the adult brain. Neural stem cells with a radial glial cell (RGC) morphology are mostly quiescent/dormant and only occasionally divide to produce transit‐amplifying cells, which divide a few times and differentiate into neurons
Figure 3
Figure 3
Dynamic expression of Notch signaling genes in active neural stem cells. Notch signaling activates the expression of Hes1, which oscillates with 2–3‐hr periodicity regulated by negative feedback of Hes1 protein. Hes1 oscillations periodically repress the expression of proneural genes and Dll1. Therefore, these genes are also expressed in an oscillatory manner (shown on the right)
Figure 4
Figure 4
Optogenetic expression of the proneural gene Ascl1. (a) Optogenetic Light‐ON system. Under dark conditions, hGAVPO is an inactive monomer. Upon blue‐light illumination, hGAVPO forms a dimer, binds to the upstream activation sequence (UAS) promoter, and activates the expression of downstream genes. (b) The Light‐ON system can differentially induce oscillatory and sustained Ascl1 expression by changing blue light illumination patterns. Ascl1 activates proliferation of neural stem cells (NSC) when its expression is oscillatory, and induces neuronal differentiation when its expression is sustained
Figure 5
Figure 5
Mutual activation of Notch signaling by oscillations. When Ascl1/Neurog2 are high in a neural stem cell (cell 1), they induce the expression of Dll1, which activates Notch signaling in a neighboring neural stem cell (cell 2). In this neighboring cell, activated Notch signaling induces the expression of Hes1, which represses Ascl1/Neurog2 and Dll1 expression. However, due to the 2–3‐hr periodicity of oscillations, Hes1 levels soon become lower, enabling Ascl1/Neurog2 and Dll1 to be expressed once again, which activates Notch signaling in the first cell (cell 1). In this way, neighboring cells (cell 1 and cell 2) can mutually activate Notch signaling via Dll1 oscillations. NICD, Notch intracellular domain
Figure 6
Figure 6
Gene expression dynamics during neurogenesis and myogenesis in adults. (a) Expression dynamics of Hes1 and Ascl1 during neurogenesis. (b) Expression dynamics of Hes1 and MyoD during myogenesis
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