[Nat Commun.]Intracellular trafficking of Notch orchestrates temporal dynamics of Notch activity in the fly brain

Intracellular trafficking of Notch orchestrates temporal dynamics of Notch activity in the fly brain Nat Commun. 2021 Apr 7;12(1):2083. doi: 10.1038/s41467-021-22442-3. Authors Miaoxing Wang # 1 , Xujun Han # 1 , Chuyan Liu 2 , Rie Takayama 1 , Tetsuo Yasugi 1 , Shin-Ichiro Ei 3 , Masaharu Nagayama 4 , Yoshitaro Tanaka 5 , Makoto Sato 6 7 Affiliations 1 Mathematical Neuroscience Unit, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, Ishikawa, Japan. 2 Laboratory of Developmental Neurobiology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan. 3 Department of Mathematics, Faculty of Science, Hokkaido University, Sapporo, Hokkaido, Japan. 4 Research Institute for Electronic Science, Research Center of Mathematics for Social Creativity, Hokkaido University, Sapporo, Hokkaido, Japan. 5 Department of Complex and Intelligent Systems, School of Systems Information Science, Future University Hakodate, Hakodate, Hokkaido, Japan. 6 Mathematical Neuroscience Unit, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, Ishikawa, Japan. makotos@staff.kanazawa-u.ac.jp. 7 Laboratory of Developmental Neurobiology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan. makotos@staff.kanazawa-u.ac.jp. # Contributed equally. PMID: 33828096 DOI: 10.1038/s41467-021-22442-3 Abstract 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.