| Project/Area Number |
11480230
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurochemistry/Neuropharmacology
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| Research Institution | University of Tokyo |
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Principal Investigator |
NAKAFUKU Masato University of Tokyo, Graduate School of Medicine, associate professor, 大学院・医学系研究科, 助教授 (80202216)
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| Co-Investigator(Kenkyū-buntansha) |
SHIMAMURA Kenji University of Tokyo, Graduate School of Medicine, instructor, 大学院・医学系研究科, 講師 (70301140)
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| Project Period (FY) |
1999 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥15,500,000 (Direct Cost: ¥15,500,000)
Fiscal Year 2000: ¥5,600,000 (Direct Cost: ¥5,600,000)
Fiscal Year 1999: ¥9,900,000 (Direct Cost: ¥9,900,000)
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| Keywords | neural development / transcription factor / neural stem cell / neuron / glia / bHLH factor / Notch |
|---|
| Research Abstract |
Multipotential neural stem cells serve as the origin of diverse cell types during genesis of the mammalian central nervous system (CNS). During early development, stem cells self-renew and increase their total cell numbers without overt differentiation. At later stages, the cells withdraw from this self-renewal mode, and are fated to differentiate into neurons and glia in a spatially and temporally regulated manner. However, the molecular mechanisms underlying this important step in cell differentiation remain poorly understood. In this study, we first presented evidence that the expression and function of the neural-specific transcription factors Mash1 and Prox1 are involved in this process. In vivo Mash1-and Prox1-expressing cells were defined as a transient proliferating population that was molecularly distinct from self-renewing stem cells. By taking advantage of in vitro culture systems, we showed that induction of Mash1 and Prox1 coincided with an initial step of differentiation
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of stem cells. Furthermore, forced expression of Mash1 led to the down-regulation of nestin, a marker for undifferentiated neuroepithelial cells, and up-regulation of Prox1, suggesting that Mash1 positively regulates cell differentiation. In support of these observations in vitro, we found specific defects in cellular differentiation and loss of expression of Prox-1 in the developing brain of Mash-1 mutant mice in vivo. Thus, we proposed that induction of Mash1 and Prox1 is one of the critical molecular events that control early development of the CNS.Next we demonstrated that intercellular signaling through the cell surface receptor Notch play an important role in regulating differentiation of neural stem cells. Notch appears to negatively regulate multiple steps of neurogenesis through distinct intracellular signaling pathways involving the transcription factor Hes1/5 and a novel signaling protein Deltex1. Thus cell fate determination of neural stem cells is under both positive and negative control involving multiple regulatory molecules. Less
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