Nuclear architecture in the long-term maintenance of brain function and brain aging
Previous and Current Research
- How is the brain organized in a temporally and spatially controlled manner?
- How do brain cells maintain their cellular identities/plasticity in our life long after they are generated during development?
- How aging and age-related neurodegenerative diseases impact on cellular identity and plasticity in the brain?
Elucidating theses questions is fundamental to understanding brain development and aging.
Previous research – temporal and spatial regulation of brain development
In my PhD work, I investigated how the initiation of neural circuit formation is regulated. Using mouse sensory systems, I found that the birthing process triggers the initiation of sensory circuit formation through serotonin signaling. Although birth is the most dramatic environmental change that a mammal will experience, little was known about its importance to brain development. The findings highlight a novel role of birth-serotonin signaling and its possible link to birth defects in brain development (Toda et al., Dev. Cell 2013).
During post-doctoral fellow, I first addressed how the human cortex has expanded and acquired its stereotypical folding pattern during evolution. I found that the expansion of neural progenitor populations within specific regions underlies the stereotypical patterns of cortical folding (Toda et al., Sci. Reports, 2016; Matsuda and Toda et al., Sci. Reports, 2015).
Current research – long-term maintenance of neural identity and plasticity
These studies of brain development set the stage for my current research efforts, which are focused on understanding the maintenance of neural identity and plasticity. Neural identity is initially specified by key transcription factors (TFs) and this neural identify must be maintained throughout life. To achieve robust cell type-specific gene regulation, there must be a structural platform that enables these TFs to maintain both a specific pattern of gene expression and neural identity. Strikingly, each neural cell type exhibits a distinct nuclear architecture, which refers to the non-random positioning of lineage-specific genes and heterochromatin/euchromatin within the nucleus (Fig 1). Neural stem cells (NSCs) possess a unique nuclear architecture, and upon differentiation, it is dramatically re-organized in a cell type-specific manner (Fig 1). The unique nuclear architectures may thus work as a structural constraint of the key TFs’ accessibility that enables them to maintain cell type-specific transcriptional landscapes.
Nuclear architecture is regulated by nuclear structural proteins such as nuclear pore complex proteins (nucleoporins) and nuclear lamins, which are identified as long-live proteins. Thus, these nuclear structural proteins could work as a structural platform for stable cell type-specific gene regulation. In our recent work, we found that Nup153, one of the nucleoporins, is essential for the maintenance of NSC’s proliferative state and multi-potency (Fig. 2; Toda et al., Cell Stem Cell 2017). Using super-resolution imaging and ChIP-seq, we also discovered that Nup153 preferentially interacts and cooperates with Sox2, a key TF for the maintenance of NSCs, to directly regulate the genetic program of NSCs. Thus, our finding indicates nucleoporin-directed nuclear architecture could be a novel fundamental epigenetic mechanism underlying the maintenance of cellular identity.
Future Projects and Goals
Aging is one of the most critical risk factors for neurological and psychiatric diseases. However, the biological links between physiological aging and pathological development are still largely unknown. We aim at elucidating this link between the fundamental mechanism underlying the long-term maintenance of neural identity/plasticity and effects of aging on that. To this end, we will focus on the following three key projects:
- Elucidating nucleoporins/lamins-directed nuclear architecture underlying the long-term maintenance of cellular identity in neurons and adult neural stem cells.
- Uncovering nucleoporins/lamins-directed nuclear architecture underlying neural plasticity in neurons.
- Investigating how aging and neurodegenerative diseases affect identified mechanisms from molecular to behavioral levels.
Methodological and Technical Expertise
- Cell culture (Neural stem cells, Neurons)
- Neurobiological technology (Viral genetic manipulation, Neural circuit tracing, immunohistochemistry)
- Transcriptomics and Epigenomics
- High-resolution and Super-resolution imaging
- Behavioral analyses
Toda T, Hsu JY, Linker SB, Hu L, Schafer ST, Mertens J, Jacinto FV, Hetzer MW, Gage FH
Nup153 interacts with Sox2 to enable bimodal gene regulation and maintenance of neural progenitor cells.
Cell Stem Cell, 21, 5, 618-634 (2017)
Toda T, Parylak S, Linker SB, Gage FH
The role of adult hippocampal neurogenesis in brain health and disease
Molecular Psychiatry, (2018)
Toda T, Shinmyo Y, Duong TAD, Masuda K, Kawasaki H
An essential role of SVZ progenitors in cortical folding in gyrencephalic mammals.
Scientific Reports, 6:29578. (2016)
Toda T, Homma D, Tokuoka H, Hayakawa I, Sugimoto Y, Ichinose H, Kawasaki H
Birth regulates the initiation of sensory map formation through serotonin signaling.
Developmental Cell, 27, 32-46. (2013)
Sehara K*, Toda T*, Iwai L*, Wakimoto M, Tanno K, Matsubayashi Y Kawasaki H
Whisker-related axonal patterns and plasticity of layer 2/3 neurons in the mouse barrel cortex.
Journal of Neuroscience, 30, 3082–3092 (2010)