Presentation Information
[SS11-02]Gene expression dynamics during mammalian neural development
*Hiromi Shimojo1, Ryoichiro Kageyama2 (1. Osaka University (Japan), 2. RIKEN (Japan))
Keywords:
Oscillation,Notch signaling,Neurogenesis,Somitogenesis,Hes
Notch-Hes signaling is important in regulating somitogenesis as a segmentation clock. Clock gene Hes7 is expressed oscillatory, regulated by a transcriptional negative feedback loop. However, whether Hes gene expression oscillates during other developmental processes and the function of the oscillatory expression remained unknown. During neural development, Notch-Hes signaling is important in maintaining neural progenitor cells. Hes1 represses the expression of proneural genes, Neurogenin2 (Neurog2), and Notch ligand Delta-like1 (Dll1) in neural progenitor cells, maintaining the undifferentiated states of neural progenitor cells. Previously, we found that the expression of Hes1 oscillated in neural progenitor cells using live cell imaging. We found that Hes1 oscillation induced oscillatory expressions of the downstream target genes, Neurog2 and Dll1, by periodic repression, and their cyclic expressions led to mutual activation of Notch signaling between neighboring cells and regulated the maintenance of a group of neural progenitor cells in the embryonic cortex. Neurog2 is expressed in neural progenitors and induces neuronal differentiation; however, the oscillatory expression of Neurog2 maintained neural progenitor cells, and its sustained expression induced neuronal differentiation. Recently, we found the oscillatory expression of Neurog2 induced the accumulation of Tbr2, one of target genes of Neurog2, and the accumulated Tbr2 protein led to down-regulation of Hes1 and Notch signaling in neural progenitor cells, inducing neuronal differentiation.
Furthermore, we focused on the expression dynamics of Notch ligand Dll1 during somitogenesis and neurogenesis. We found that Dll1 protein expression oscillated in both developmental processes. Because Dll1 is an important molecule to transmit Notch signaling between neighboring cells, we changed Dll1 expression dynamics during embryogenesis. We found that accelerated and delayed Dll1 expression led to damped oscillation of Dll1, a phenomenon known as “amplitude/oscillation death” of coupled oscillators in mathematical modeling. Under this condition, Hes1 and Hes7 oscillations were also damped, leading to defects in somitogenesis and neurogenesis. These results indicated that the appropriate timing of Dll1 expression is critical for the oscillatory networks and the functional significance of oscillatory cell-cell interactions in tissue morphogenesis.
Furthermore, we focused on the expression dynamics of Notch ligand Dll1 during somitogenesis and neurogenesis. We found that Dll1 protein expression oscillated in both developmental processes. Because Dll1 is an important molecule to transmit Notch signaling between neighboring cells, we changed Dll1 expression dynamics during embryogenesis. We found that accelerated and delayed Dll1 expression led to damped oscillation of Dll1, a phenomenon known as “amplitude/oscillation death” of coupled oscillators in mathematical modeling. Under this condition, Hes1 and Hes7 oscillations were also damped, leading to defects in somitogenesis and neurogenesis. These results indicated that the appropriate timing of Dll1 expression is critical for the oscillatory networks and the functional significance of oscillatory cell-cell interactions in tissue morphogenesis.