Maintenance of neural stem-progenitor cells by the lysosomal biosynthesis regulators TFEB and TFE3 in the embryonic mouse telencephalon
Abstract
Lysosomes have recently been implicated in regulation of quiescence in adult neural stem cells (NSCs). Whether lysosomes regulate the differentiation of neural stem-progenitor cells (NPCs) in the embryonic brain has remained unknown, however. We here show that lysosomes are more abundant in rapidly dividing NPCs than in differentiating neurons in the embryonic mouse neocortex and ganglionic eminence. The genes for TFEB and TFE3, master regulators of lysosomal biosynthesis, as well as other lysosome-related genes were also expressed at higher levels in NPCs than in differentiating neurons. Anatomic analysis revealed accumulation of lysosomes at the apical and basal endfeet of NPCs. Knockdown of TFEB and TFE3, or that of the lysosomal transporter Slc15a4, resulted in premature differentiation of neocortical NPCs. Conversely, forced expression of an active form of TFEB (TFEB-AA) suppressed neuronal differentiation of NPCs in association with upregulation of NPC-related genes. These results together point to a previously unappreciated role for TFEB and TFE3, and possibly for lysosomes, in maintenance of the undifferentiated state of embryonic NPCs. We further found that lysosomes are even more abundant in an NPC subpopulation that rarely divides and includes the embryonic origin of adult NSCs than in the majority of NPCs that divide frequently for construction of the embryonic brain, and that overexpression of TFEB-AA also suppressed the cell cycle of neocortical NPCs. Our result…
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Exopher formation and extracellular proteostasis have been discovered in recent years.
“Newer mechanisms to manage proteostasis, such as exopher formation and extracellular proteostasis, have been discovered in recent years.165,166”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [165]
Cites
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Embryonic origin of postnatal neural stem cells
Fuentealba, L. C., Rompani, S. B., Parraguez, J. I., Obernier, K., Romero, R., Cepko, C. L., & Alvarez-Buylla, A. (2015) · Cell · doi:10.1016/j.cell.2015.05.041 · Cited by 488 · cited 1× · see citing works
“aside during development and later become adult neural stem cells (NSCs) in the mouse subventricular zone (SVZ).(5,6) This subpopulation of NPCs (designated the embryonic origin of adult NSCs) must be maintained for a longer period in order to subserve life-long neuro-”
BackgroundSlowly dividing neural progenitors are an embryonic origin of adult neural stem cells
Furutachi, S., Miya, H., Watanabe, T., Kawai, H., Yamasaki, N., Harada, Y., Imayoshi, I., Nelson, M., Nakayama, K. I., Hirabayashi, Y., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.3989 · Cited by 329 · see citing works
Lysosomal Signaling Licenses Embryonic Stem Cell Differentiation via Inactivation of Tfe3
Villegas, F., Lehalle, D., Mayer, D., Rittirsch, M., Stadler, M. B., Zinner, M., Olivieri, D., Vabres, P., Duplomb-Jego, L., De Bont, E. S. J. M., et al. (2019) · Cell Stem Cell · doi:10.1016/j.stem.2018.11.021 · Cited by 110 · see citing works
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Lane-Donovan, C., Paredes, M., & Kao, A. W. (2025) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2025.102854 · Cited by 3 · see citing works
- Authors
- Yuizumi, N., Harada, Y., Kuniya, T., Sunabori, T., Koike, M., Wakabayashi, M., Ishihama, Y., Suzuki, Y., Kawaguchi, D., & Gotoh, Y.
- Affiliations
- The University of Tokyo (JP)
- Juntendo University (JP)
- National Cerebral and Cardiovascular Center (JP)
- Kyoto University (JP)
- International Research Center for Neurointelligence, The University of Tokyo (JP)
- Corresponding author
- Kawaguchi, Daichi
- Gotoh, Yukiko
- Venue
- Stem Cells
- Publisher
- Oxford University Press (OUP)
- Published
- 2021-03-10
- Volume
- 39
- Issue
- 7
- Pages
- 929-944
- ISSN
- 1066-5099 (ISSN-L)
- 1549-4918
- OpenAlex
- W3132631671
- Cited by
- 23
- References
- 5
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 8 · 2023: 5 · 2022: 3 · 2021: 2
- FWCI
- 1.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Stem Cells (publishedVersion)
- PubMed (publishedVersion)
- Funders
- AMED-CREST of the Japan Agency for Medical Research and Development (JP20gm1310004)
- Japan Society for the Promotion of Science (JP15H05773, JP16H06280, JP16H06479, JP16H06481, JP17J09837, JP18K06477, JP19J22938)
- Ministry of Education, Culture, Sports, Science and Technology
- Uehara Memorial Foundation
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- neural stem/progenitor cells, lysosomes, TFEB, TFE3, SLC15A4, neuronal differentiation, embryonic neocortex, ganglionic eminence, telencephalon, cell cycle regulation, adult neural stem cells, stem cell quiescence
- MeSH terms
- Animals, Cell Differentiation, Lysosomes, Neocortex, Membrane Transport Proteins, Mice, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Neural Stem Cells
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