Mathematical Neuroscience Unit, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, Ishikawa, Japan.
Laboratory of Developmental Neurobiology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan.
Nat Commun. 2021 Apr 7;12(1):2083. doi: 10.1038/s41467-021-22442-3.
While Delta non-autonomously activates Notch in neighboring cells, it autonomously inactivates Notch through cis-inhibition, the molecular mechanism and biological roles of which remain elusive. The wave of differentiation in the Drosophila brain, the 'proneural wave', is an excellent model for studying Notch signaling in vivo. Here, we show that strong nonlinearity in cis-inhibition reproduces the second peak of Notch activity behind the proneural wave in silico. Based on this, we demonstrate that Delta expression induces a quick degradation of Notch in late endosomes and the formation of the twin peaks of Notch activity in vivo. Indeed, the amount of Notch is upregulated and the twin peaks are fused forming a single peak when the function of Delta or late endosomes is compromised. Additionally, we show that the second Notch peak behind the wavefront controls neurogenesis. Thus, intracellular trafficking of Notch orchestrates the temporal dynamics of Notch activity and the temporal patterning of neurogenesis.
虽然 Delta 通过顺式抑制非自主地激活邻近细胞中的 Notch，但它通过顺式抑制自主地使 Notch 失活，其分子机制和生物学作用仍然难以捉摸。果蝇大脑中的分化波，即“神经前波”，是研究 Notch 信号通路体内的绝佳模型。在这里，我们表明 cis 抑制的强非线性可在体内重现神经前波之后 Notch 活性的第二个峰值。基于这一点，我们证明 Delta 表达诱导 Notch 在晚期内体中的快速降解，并在体内形成 Notch 活性的双峰。事实上，当 Delta 或晚期内体的功能受到损害时， Notch 的数量上调，双峰融合形成单个峰。此外，我们还表明，波阵面后的第二个 Notch 峰控制神经发生。因此，Notch 的细胞内运输协调了 Notch 活性的时间动态和神经发生的时间模式。
