Notch シグナル ノ オシレーション ニ ヨッテ シンケイ ゼンク サイボウ ノ イジ ガ セイギョサレル

京都大学0048新制・課程博士博士(医学)甲第13736号医博第3251号新制||医||968(附属図書館)UT51-2008-C652京都大学大学院医学研究科病理系専攻(主査)教授 渡邉 大, 教授 髙橋 良輔, 教授 富田 直秀学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA

Dynamic expression and roles of Hes factors in neural development.

The basic helix-loop-helix factors Hes1 and Hes5 repress the expression of proneural factors such as Ascl1, thereby inhibiting neuronal differentiation and maintaining neural progenitor cells (NPCs). Hes1 expression oscillates by negative feedback with a period of about 2-3 h in proliferating NPCs. Induction of sustained expression of Hes1 in NPCs inhibits their cell-cycle progression, suggesting that the oscillatory expression of Hes1 is important for the proliferation of NPCs. Hes1 oscillation drives the oscillatory expression of proneural factors such as Ascl1 by periodic repression. By contrast, in differentiating neurons, Hes1 expression disappears and the expression of proneural factors is up-regulated and sustained. A new optogenetics approach that induces Ascl1 expression by blue light illumination demonstrated that sustained expression of Ascl1 induces neuronal differentiation, whereas oscillatory expression of Ascl1 activates the proliferation of NPCs. These results together indicate that Hes1 regulates the oscillatory versus sustained expression of the proneural factor Ascl1, which in turn regulates the proliferation of NPCs and the subsequent processes of cell-cycle exit and neuronal fate determination, depending on the expression dynamics

Dynamic regulation of Notch signaling in neural progenitor cells

In the developing nervous system, differentiating neurons express Delta and activate Notch signaling in their neighboring cells. As a result of Notch activation, neuronal differentiation is inhibited in neighboring cells and they remain neural progenitor cells. Thus, differentiation of neurons and maintenance of neural progenitor cells are well balanced owing to Notch signaling. Recent studies revealed that Notch signaling is under the control of more complex and dynamic regulation than previously thought, such as cell cycle dependent activation and oscillating gene expression. We discuss here recent advances in understanding how Notch signaling is regulated in the developing nervous system and what outcome each type of regulation of Notch signaling leads to. We highlight the role of Notch signaling in proliferation and differentiation of neural progenitor cells

The significance of gene expression dynamics in neural stem cell regulation

Neural stem cells (NSCs) actively proliferate and generate neurons and glial cells (active state) in the embryonic brain, whereas they are mostly dormant (quiescent state) in the adult brain. The expression dynamics of Hes1 are different between active and quiescent NSCs. In active NSCs, Hes1 expression oscillates and periodically represses the expression of proneural genes such as Ascl1, thereby driving their oscillations. By contrast, in quiescent NSCs, Hes1 oscillations maintain expression at higher levels even at trough phases (thus continuous), thereby continuously suppressing proneural gene expression. High levels of Hes1 expression and the resultant suppression of Ascl1 promote the quiescent state of NSCs, whereas oscillatory Hes1 expression and the resultant oscillatory Ascl1 expression regulate their active state. Furthermore, in other developmental contexts, high, continuous Hes1 expression induces astrocyte differentiation or the formation of boundaries, which function as signaling centers. Thus, the expression dynamics of Hes1 are a key regulatory mechanism generating and maintaining various cell types in the nervous system

Oscillatory control of Delta-like1 in cell interactions regulates dynamic gene expression and tissue morphogenesis

Notch signaling regulates tissue morphogenesis through cell–cell interactions. The Notch effectors Hes1 and Hes7 are expressed in an oscillatory manner and regulate developmental processes such as neurogenesis and somitogenesis, respectively. Expression of the mRNA for the mouse Notch ligand Delta-like1 (Dll1) is also oscillatory. However, the dynamics of Dll1 protein expression are controversial, and their functional significance is unknown. Here, we developed a live-imaging system and found that Dll1 protein expression oscillated in neural progenitors and presomitic mesoderm cells. Notably, when Dll1 expression was accelerated or delayed by shortening or elongating the Dll1 gene, Dll1 oscillations became severely dampened or quenched at intermediate levels, as modeled mathematically. Under this condition, Hes1 and Hes7 oscillations were also dampened. In the presomitic mesoderm, steady Dll1 expression led to severe fusion of somites and their derivatives, such as vertebrae and ribs. In the developing brain, steady Dll1 expression inhibited proliferation of neural progenitors and accelerated neurogenesis, whereas optogenetic induction of Dll1 oscillation efficiently maintained neural progenitors. These results indicate that the appropriate timing of Dll1 expression is critical for the oscillatory networks and suggest the functional significance of oscillatory cell–cell interactions in tissue morphogenesis

Different types of oscillations in Notch and Fgf signaling regulate the spatiotemporal periodicity of somitogenesis

Somitogenesis is controlled by cyclic genes such as Notch effectors and by the wave front established by morphogens such as Fgf8, but the precise mechanism of how these factors are coordinated remains to be determined. Here, we show that effectors of Notch and Fgf pathways oscillate in different dynamics and that oscillations in Notch signaling generate alternating phase shift, thereby periodically segregating a group of synchronized cells, whereas oscillations in Fgf signaling released these synchronized cells for somitogenesis at the same time. These results suggest that Notch oscillators define the prospective somite region, while Fgf oscillators regulate the pace of segmentation