Ultradian oscillations in Notch signaling regulate dynamic biological events.

Notch signaling regulates many dynamic processes; accordingly, expression of genes in this pathway is also dynamic. In mouse embryos, one dynamic process regulated by Notch is somite segmentation, which occurs with a 2-h periodicity. This periodic event is regulated by a biological clock called the segmentation clock, which involves cyclic expression of the Notch effector gene Hes7. Loss of Hes7 expression and sustained expression of Hes7 result in identical and severe somite defects, suggesting that Hes7 oscillation is required for proper somite segmentation. Mathematical models of this oscillator have been used to generate and test hypothesis, helping to uncover the role of negative feedback in regulating the oscillator. Oscillations of another Notch effector gene, Hes1, plays an important role in maintenance of neural stem cells. Hes1 expression oscillates with a period of about 2-3h in neural stem cells, whereas sustained Hes1 expression inhibits proliferation and differentiation of these cells, suggesting that Hes1 oscillations are important for their proper activities. Hes1 inhibits its own expression as well as the expression of the proneural gene Neurogenin2 and the Notch ligand Delta1, driving oscillations of these two genes. Delta1 oscillations in turn maintain neural stem cells by mutual activation of Notch signaling, which re-activates Hes1 to close the cycle. Hes1 expression also oscillates in embryonic stem (ES) cells. Cells expressing low and high levels of Hes1 tend to differentiate into neural and mesodermal cells, respectively. Furthermore, Hes1-null ES cells display early and uniform neural differentiation, indicating that Hes1 oscillations act to promote multipotency by generating heterogeneity in both the differentiation timing and the fate choice. Taken together, these results suggest that Notch signaling can drive short-period oscillatory expression of Hes7 and Hes1 (ultradian oscillation) and that ultradian oscillations are important for many biological events.

Kageyama R ，Niwa Y ，Shimojo H ，Kobayashi T ，Ohtsuka T ... -  《-》

Oscillator mechanism of Notch pathway in the segmentation clock.

Somites are formed by periodic segmentation of the presomitic mesoderm (PSM). This periodic event is controlled by the segmentation clock, where Notch signaling plays an essential role. The basic helix-loop-helix factor Hes7, a Notch effector, is cyclically expressed by negative feedback and regulates cyclic expression of Lunatic fringe (Lfng), a Notch modulator. Lfng then seems to periodically inhibit Notch, leading to oscillation in Notch activity. It is thought that these coupled negative feedback loops by Hes7 and Lfng are important for sustained and synchronized oscillations in the PSM. Of interest, another Notch effector, Hes1, is cyclically expressed by many cell types such as neuroblasts, suggesting that this clock is widely distributed and regulates many biological events. This review summarizes the recent finding about roles and mechanism of Notch signaling in the segmentation clock and discusses the significance of Hes1 oscillation in non-PSM cells.

Kageyama R ，Masamizu Y ，Niwa Y 《DEVELOPMENTAL DYNAMICS》

Rhythmic gene expression in somite formation and neural development.

Kageyama R ，Niwa Y ，Shimojo H 《-》

The initiation and propagation of Hes7 oscillation are cooperatively regulated by Fgf and notch signaling in the somite segmentation clock.

Niwa Y ，Masamizu Y ，Liu T ，Nakayama R ，Deng CX ，Kageyama R ... -  《DEVELOPMENTAL CELL》

The roles and mechanism of ultradian oscillatory expression of the mouse Hes genes.

Somites, metameric structures, give rise to the vertebral column, ribs, skeletal muscles and subcutaneous tissues. In mouse embryos, a pair of somites is formed every 2h by segmentation of the anterior parts of the presomitic mesoderm. This periodic event is regulated by a biological clock called the segmentation clock, which involves cyclic expression of the basic helix-loop-helix gene Hes7. Hes7 oscillation is regulated by negative feedback with a delayed timing. This process has been mathematically simulated by differential-delay equations, which predict that negative feedback with shorter delays would abolish oscillations or produce dampened but more rapid oscillations. We found that reducing the number of introns within the Hes7 gene shortens the delay and abolishes Hes7 oscillation or results in a more rapid tempo of Hes7 oscillation, increasing the number of somites and vertebrae in the cervical and upper thoracic region. We also found that Hes1, a Hes7-related gene, is expressed in an oscillatory manner by many cell types, including fibroblasts and neural stem cells. In these cells, Hes1 expression oscillates with a period of about 2-3h, and this oscillation is important for cell cycle progression. Furthermore, in neural stem cells, Hes1 oscillation drives cyclic expression of the proneural genes Ascl1 and Neurogenin2 and regulates multipotency. Hes1 expression oscillates more slowly in embryonic stem cells, and Hes1 oscillation regulates their fate preferences. Taken together, these results suggest that oscillatory expression with short periods (ultradian oscillation) is important for many biological events.

Harima Y ，Imayoshi I ，Shimojo H ，Kobayashi T ，Kageyama R ... -  《-》