Prof. Itsuji Ajioka
- ISP2012 Lecture Course Abstract:
Deregulation of cell cycle on brain disorder
Neurons are generated from multi-potent progenitor cells (neural stem cells) during development. Once the daughter cells generated from neuronal progenitors initiate neuronal differentiation program, they become post-mitotic and non-dividing cells. This idea was suggested one century ago by Ramon y Cajal, Nobel Prize winner of 1906, and was experimentally supported by using radioactive thymidine analog, called as “neuronal birth-date study”, by Richard Sidman in 1950's. Although post-mitotic neurons are believed to be in quiescent state (G0 phase) of cell cycle until neurons die, neurons re-enter cell cycle and undergoes S phase in patients of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. In addition, when neurons cultured in vitro are forcibly re-enter cell cycle, they undergo cell death following S phase progression. Based on these facts, some researchers support the hypothesis that the cell cycle re-entering of neurons is the cause of cell death associated with neuronal degeneration.
Although neurons are believed to be non-dividing cells, neuronal tumor is not a rare tumor. RB1 is the first tumor suppressor gene cloned from the family with retinoblastoma and suppresses the transcription of the genes important for S phase progression by binding to E2F transcription factors. By using in vitro cell culture system, the molecular mechanisms of Rb pathway have been extensively revealed during these 25 years. However, in vivo study has been difficult because of the complicated compensations and redundancies among the Rb family members (Rb, p107, p130). Recently, we have carefully investigated the role of each Rb family members for retinal development by generating Rb-single (Chx10-Cre; RbLox/+; p107-/-; p130-/-), p107-single (Chx10-Cre; RbLox/Lox; p107+/-; p130-/-), and p130-single (Chx10-Cre; RbLox/Lox; p107-/-; p130+/-) mice and unexpectedly discovered that differentiated p107-single horizontal neurons, one of the retinal interneurons, proliferate and form tumors with maintaining the feature of differentiated neurons including neurites and synapses. This was the first demonstration that differentiated neurons can proliferate and form cancer while maintaining their differentiated state including neurites and synaptic connections.
Thus, neurons can proliferate in a certain situation. However, the mechanisms of how neurons are protected from cell division in general and how Rb family-deficient neurons overcome this protection and form tumors are still unknown.
In this lecture, I would like to introduce the role of cell cycle regulation in brain development. Also, I would like to introduce our recent research that addressed the mechanisms by which differentiating neurons can proliferate after the loss of Rb family members.
- Prof. Ajioka's ISP2012 Profile
- Prof. Ajioka's TMDU Research Profile:
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