Mathematical Neuroscience Unit, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa-shi, Ishikawa, Japan.
Laboratory of Developmental Neurobiology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa-shi, Ishikawa, Japan.
Adv Exp Med Biol. 2020;1218:77-91. doi: 10.1007/978-3-030-34436-8_5.
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.
Notch 介导的侧向抑制调节二元细胞命运选择，导致在各种生物学过程中形成椒盐模式。在许多情况下，Notch 信号与其他信号系统一起作用。然而，当 Notch 信号与其他信号系统结合时会发生什么情况尚不清楚。数学建模和使用简单的生物模型系统对于解决这一不确定性至关重要。在果蝇视觉中心的一波分化，即“神经前波”，伴随着 Notch 和 EGF 信号通路的活动。虽然参与侧向抑制的 Notch 信号的所有必需成分都参与神经前波，但在神经前波的进展过程中没有发现椒盐模式。相反， Notch 沿波前被激活并调节神经前波的进展。 Notch 信号如何在不形成椒盐模式的情况下控制波的传播？基于生物学证据的神经前波的数学模型表明， Notch 介导的侧向抑制在神经前波内实施，并且 EGF 的扩散作用消除了椒盐模式的形成。体内遗传实验证实了数值模拟的结果，并表明 Notch 介导的侧向抑制和 EGF 介导的反应扩散的组合使 Notch 信号能够调节神经前波的传播，从而发挥新的功能。类似的机制可能在动物发育和癌症发病机制中发现的各种生物学过程中发挥重要作用。
