Oscillatory Control of Notch Signaling in Development
The Notch effectors Hes1 and Hes7 and the Notch ligand Delta-like1 (Dll1) are expressed in an oscillatory manner during neurogenesis and somitogenesis. These two biological events exhibit different types of oscillations: anti-/out-of-phase oscillation in neural stem cells during neurogenesis and in-phase oscillation in presomitic mesoderm (PSM) cells during somitogenesis. Accelerated or delayed Dll1 expression by shortening or elongating the size of the Dll1 gene, respectively, dampens or quenches Dll1 oscillation at intermediate levels, a phenomenon known as “amplitude/oscillation death” of coupled oscillators. Under this condition, both Hes1 oscillation in neural stem cells and Hes7 oscillation in PSM cells are also dampened. As a result, maintenance of neural stem cells is impaired, leading to microcephaly, while somite segmentation is impaired, leading to severe fusion of somites and their derivatives, such as vertebrae and ribs. Thus, the appropriate timing of Dll1 expression is critical for the oscillatory expression in Notch signaling and normal processes of neurogenesis and somitogenesis. Optogenetic analysis indicated that Dll1 oscillations transfer the oscillatory information between neighboring cells, which may induce anti−/out-of-phase and in-phase oscillations depending on the delay in signaling transmission. These oscillatory dynamics can be described in a unified manner by mathematical modeling.
KeywordsOscillatory expression Neural stem cell Presomitic mesoderm Somite segmentation clock
This work was supported by Core Research for Evolutional Science and Technology (R.K.), Grant-in-Aid for Scientific Research on Innovative Areas (MEXT 16H06480 to R.K., MEXT 24116705 to H.S., and MEXT 26119708 to A.I.), Scientific Research (A) (JSPS 24240049) (R.K.), Young Scientists (A) (JSPS 15H05326) (A.I.) and Young Scientists (B) (JSPS 24700354) (H.S.) and Platform for Dynamic Approaches to Living System from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
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