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Review
. 2021 May;288(10):3082-3093.
doi: 10.1111/febs.15555. Epub 2020 Sep 15.

Lysosomes and signaling pathways for maintenance of quiescence in adult neural stem cells

Taeko Kobayashi  1   2   3 , Ryoichiro Kageyama  1   2   3   4
Affiliations
Review

Lysosomes and signaling pathways for maintenance of quiescence in adult neural stem cells

Taeko Kobayashi et al. FEBS J. 2021 May.

Abstract

Quiescence is a cellular strategy for maintaining somatic stem cells in a specific niche in a low metabolic state without senescence for a long period of time. During development, neural stem cells (NSCs) actively proliferate and self-renew, and their progeny differentiate into both neurons and glial cells to form mature brain tissues. On the other hand, most NSCs in the adult brain are quiescent and arrested in G0/G1 phase of the cell cycle. Quiescence is essential in order to avoid the precocious exhaustion of NSCs, ensuring a sustainable source of available stem cells in the brain throughout the lifespan. After receiving activation signals, quiescent NSCs reenter the cell cycle and generate new neurons. This switching between quiescence and proliferation is tightly regulated by diverse signaling pathways. Recent studies suggest significant involvement of cellular proteostasis (homeostasis of the proteome) in the quiescent state of NSCs. Proteostasis is the result of integrated regulation of protein synthesis, folding, and degradation. In this review, we discuss regulation of quiescence by multiple signaling pathways, especially bone morphogenetic protein and Notch signaling, and focus on the functional involvement of the lysosome, an organelle governing cellular degradation, in quiescence of adult NSCs.

Keywords: adult neural stem cell; lysosome; proteostasis; quiescence; signaling.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Two NSC niches, the SVZ and DG, in the adult mouse brain. Schematic representation of a lateral view of the whole adult mouse brain from the olfactory bulb (left) to cerebellum (right). Coronal planes dissected at lines (a) and (b) are shown in panels (A) and (B), respectively, on the right. The two NSC niches are labeled in blue lines, highlighting the SVZ near the lateral ventricle (A) and the DG in the hippocampus (B). Ventricles in the brain sections appear in white in panels (A) and (B). The detailed compositions of niches are represented in panels (C) and (D) as enlarged views marked by red squares (c in A) and (d in B), respectively. Panel (C) displays the SVZ niche, which is located near the lateral sides of the lateral ventricles. NSCs (blue) face the CSF in the lateral ventricle together with ependymal cells and elongate their projection to blood vessels (red). Panel (D) displays the DG niche, surrounded by the granule cell layers (gray) and hilus. NSCs are located in the subgranular zone next to the granule cell layer and elongate radial fibers, resulting in a radial glial morphology. NSCs in both niches self‐renew, differentiate into progenitor cells (green), and give rise to mature neurons (orange).
Fig. 2
Fig. 2
BMP and Notch signaling cascades. (A) Canonical pathway of BMP signaling. BMPR bind to BMP ligands, and transduce signals via SMAD molecules, which ultimately enhance Id gene expression. Noggin sequesters BMP and antagonizes BMP signaling. (B) Canonical pathway of Notch signaling. Notch receptors bind to ligands on neighboring cells, inducing gamma‐secretase‐mediated cleavage in the signal‐receiving cells (lower). Cleaved Notch receptor (NICD) translocates into the nucleus and activates the expression of Hes genes.
Fig. 3
Fig. 3
The lysosome functions as a degradative organelle and a signaling hub. (A) Lysosomes digest cargo from endosomes and autophagosomes in the acidic lumen. The endolysosomal pathway degrades biomolecules, including membrane receptors, in lysosomes following their internalization by endocytosis. Autophagy encloses cytoplasmic materials, including organelles, into autophagosomes, which fuse with lysosomes where their contents are digested. Lysosomes secrete their contents via lysosomal exocytosis. Lysosomes function as a signaling hub for nutrient sensing. The gray square is enlarged in panel B. (B) The lysosome is a hub where signaling molecules localize and transduce their signals. v‐ATPase maintains a low pH by pumping protons. Nutrient‐rich conditions activate Ragulator‐RAG, which recruits and activates mammalian target of rapamycin complex 1 (mTORC1) to lysosomes. Activated mTORC1 (pink) inhibits lysosomal biogenesis through inhibitory phosphorylation of TFEB. Low nutrient concentration results in inactivation of mTORC1 and activation of TFEB, thereby inducing expression of lysosomal genes.
Fig. 4
Fig. 4
Lysosomal regulation of NSC quiescence. To maintain proteostasis, active NSCs have higher proteasomal activity and lower lysosomal activity, while quiescent NSCs have lower proteasomal activity and higher lysosomal activity. Quiescent NSCs contain more lysosomes, but lysosomal abundance decreases over the course of the aging process. On the other hand, the level of protein aggregates and ROS increases with age, in turn affecting the depth of quiescence. In active NSCs, TFEB activation induces quiescence, whereas in quiescent NSCs, it rejuvenates the cells and decreases the abundance of aggregates. Thus, lysosomes serve as a switch for maintaining NSC quiescence.
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