Research
How is brain function maintained throughout life?
In this increasingly aging society, it is imperative to keep healthy brain functions even in old age. Quiescence in adult neural stem cells might be crucial to addressing this question.
Most neural stem cells (more than 90%) in the adult brain are quiescent. It remains unclear why so many neural stem cells (NSCs) persist in the quiescent state in the adult brain. Quiescence is essential in order to avoid precocious exhaustion of neural stem cells, ensuring a sustainable source of available stem cells in a specific niche without senescence throughout the lifespan. Importantly, the reactivation of NSCs from quiescent to proliferating significantly decreases with age.
Quiescence of adult NSCs istightly regulated by intrinsic and extrinsic factors, and diverse signaling from local NSC niches are involved in this process. I aim to reveal the mechanism of adult NSC maintenance from novel viewpoints of the ‘lysosome’ and ‘extracellular stiffness’ and to improve the functional decline of NSCs with age.
I will clarify the molecular and physical mechanisms for maintenance of NSCs based on lysosomal control and contribute to developing new therapeutic tools for degenerative brain diseases, such as Alzheimer’s disease.
Published Papers
Research Papers
Zhang, J., Uchiyama, J., Imami, K., Ishihama, Y., Kageyama, R. and *Kobayashi,T.
Novel roles of small extracellular vesicles in regulating the quiescence and proliferation of neural stem cells. bioRxiv (2021) https://www.biorxiv.org/content/10.1101/2021.08.20.456431v1
*Kobayashi, T., Piao, W., Takamura, T., Kori, H., Miyachi, H., Kitano, S., Iwamoto, Y., Yamada, M., Imayoshi, I., Shioda, S., Ballabio, A., and *Kageyama, R.
Enhanced lysosomal degradation maintains the quiescent state of neural stem cells.
Nat. Commun. 10, 5446. (2019)
Komori, H., Golden, K. L., Kobayashi, T., Kageyama, R., and *Lee, C.-Y.
Multilayered gene control drives timely exit from the stem cell state in uncommitted progenitors during Drosophila asymmetric neural stem cell division.
Genes Dev. 32, 1–12. (2018)
*Kobayashi, T., Iwamoto, Y., Takashima, K, Isomura, A., Kosodo, Y., Kawakami, K., Nishioka, T., Kaibuchi, K., and *Kageyama, R.
Deubiquitinating enzymes regulate Hes1 stability and neuronal differentiation.
FEBS J. 282, 2475-2487. (2015)
Nagashima, F., Suzuki, I. K., Shitamukai, A., Sakaguchi, H., Iwashita, M., Kobayashi, T., Tone, S., Toida, K., Vanderhaeghen, P. and *Kosodo, Y.
Novel and robust transplantation reveals the acquisition of polarized processes by cortical cells derived from mouse and human pluripotent stem cells.
Stem Cells Dev. 23, 2129-2142. (2014)
Ueo, T., Imayoshi, I., Kobayashi, T., Ohtsuka, T., Seno, H., Nakase, H., Chiba, T. and *Kageyama, R.
The role of Hes genes in intestinal development, homeostasis and tumor formation.
Development. 139, 1071-1082. (2012)
*Kobayashi, T. and *Kageyama, R.
Hes1 regulates embryonic stem cell differentiation by suppressing Notch signaling.
Genes Cells. 15, 689-698. (2010)
*Kobayashi, T., Mizuno, H., Imayoshi, I., Furusawa, C., Shirahige, K. and *Kageyama, R.
The cyclic gene Hes1 contributes to diverse differentiation responses of embryonic stem cells.
Genes Dev. 23, 1870-1875. (2009)
Ishii, A., Kobayashi, T. and *Kageyama, R.
Requirement of multiple lysine residues for the transcriptional activity and the instability of Hes7.
Biochem Biophys Res Commun. 372, 142-6. (2008)
Kobayashi, T., Manno, A. and *Kakizuka, A.
Involvement of valosin-containing protein (VCP)/p97 in the formation and clearance of abnormal protein aggregates.
Genes Cells. 12, 889-901. (2007)
Kobayashi, T., Tanaka, K., Inoue, K. and *Kakizuka, A.
Functional ATPase activity of p97/valosin-containing protein (VCP) is required for the quality control of endoplasmic reticulum in neuronally differentiated mammalian PC12 cells.
J. Biol. Chem. 277, 47358-65. (2002)
Kobayashi, T., Takahashi, Y. and *Ito, K.
Identification of a segment of DsbB essential for its respiration-coupled oxidation.
Molecular Microbiology 39, 158-165. (2001)
Kobayashi, T. and *Ito, K.
Respiratory chain strongly oxidizes the CXXC motif of DsbB in the Escherichia coli dislfide bond formation pathway.
The EMBO Journal. 18, 1192-1198. (1999)
Kobayashi, T., Kishigami, S., Sone, M., Inokuchi, H., Mogi, T. and *Ito, K.
Respiratory chain is required to maintain oxidized states of DsbA-DsbB disulfide bond formation system in aerobically growing Escherichia coli cells.
Proc. Natl. Acad. Sci. USA 94, 11857-11862. (1997)
Review papers
*Kobayashi, T. and *Kageyama, R.
Lysosomes and signaling pathways for maintenance of quiescence in adult neural stem cells.
FEBS J. in press.
*Kobayashi, T. and *Kageyama, R.
Expression dynamics and functions of Hes genes in development and diseases.
Curr Top Dev Biol. 110, 263-283. (2014)
Harima, Y., Imayoshi, I., Shimojo, H., Kobayashi, T., and Kageyama, R.
The roles and mechanism of ultradian oscillatory expression of the mouse Hes genes.
Semin Cell Dev Biol. 34, 85-90. (2014)
*Kobayashi, T. and *Kageyama, R.
Hes1 oscillations contribute to heterogeneous differentiation responses in embryonic stem cells.
Genes. 2, 219-228 (2011)
*Kageyama, R., Niwa, Y., Shimojo, H., Kobayashi, T., Ohtsuka, T.
Ultradian oscillations in Notch signaling regulate dynamic biological events.
Curr. Top. Dev. Biol. 92, 311-331. (2010)
*Kobayashi, T. and *Kageyama, R.
Hes1 oscillation: making variable choices for stem cell differentiation.
Cell Cycle. 9, 207-8. (2010)
*Kobayashi, T. and *Kageyama, R.
Dynamic advances in NF-kappaB signaling analysis.
Sci Signal. 2, pe47. (2009)
*Kageyama, R., Ohtsuka, T. and Kobayashi, T.
Roles of Hes genes in neural development.
Dev Growth Differ. 50 Suppl 1, S97-103. (2008)
*Kageyama, R., Ohtsuka, T. and Kobayashi, T.
The Hes gene family: repressors and oscillators that orchestrate embryogenesis. Development. 134, 1243-51. (2007)
Kobayashi, T. and *Kakizuka, A.
Molecular analyses of Machado-Joseph disease.
Cytogenet Genome Res. 100, 261-75. (2003)