Regulation of Proneural Wave Propagation Through a Combination of Notch-Mediated Lateral Inhibition and EGF-Mediated Reaction Diffusion
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Notch-mediated lateral inhibition regulates binary cell fate choice, resulting in salt-and-pepper pattern formation during various biological processes. In many cases, Notch signaling acts together with other signaling systems. However, it is not clear what happens when Notch signaling is combined with other signaling systems. Mathematical modeling and the use of a simple biological model system will be essential to address this uncertainty. A wave of differentiation in the Drosophila visual center, the “proneural wave,” accompanies the activity of the Notch and EGF signaling pathways. Although all of the Notch signaling components required for lateral inhibition are involved in the proneural wave, no salt-and-pepper pattern is found during the progression of the proneural wave. Instead, Notch is activated along the wave front and regulates proneural wave progression. How does Notch signaling control wave propagation without forming a salt-and-pepper pattern? A mathematical model of the proneural wave, based on biological evidence, has demonstrated that Notch-mediated lateral inhibition is implemented within the proneural wave and that the diffusible action of EGF cancels salt-and-pepper pattern formation. The results from numerical simulation have been confirmed by genetic experiments in vivo and suggest that the combination of Notch-mediated lateral inhibition and EGF-mediated reaction diffusion enables a novel function of Notch signaling that regulates propagation of the proneural wave. Similar mechanisms may play important roles in diverse biological processes found in animal development and cancer pathogenesis.
KeywordsNotch Delta Lateral inhibition EGF Reaction diffusion JAK/STAT Noise resistance Drosophila Visual system Proneural wave Mathematical model
We thank Masaharu Nagayama and Yoshitaro Tanaka for their critical comments. This work was supported by Core Research for Evolutional Science and Technology (CREST) from the Japan Science and Technology Agency (JST) (Grant JPMJCR14D3 to M.S.); Grants-in-Aid for Scientific Research on Innovative Areas and Grants-in-Aid for Scientific Research (B) and (C) from the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT) (Grants JP17H05739, JP17H05761, JP17H03542, and JP19H04771 to M.S.; and Grants JP18H05099, 19K06674, and 19H04956 to T.Y.); Takeda Science Foundation (to M.S. and T.Y.); and a Grant for Cooperative Research on ‘Network Joint Research Center for Materials and Devices’ (to M.S.).