Abstract
ABSTRACTThe evolutionarily conserved Notch signaling pathway plays crucial roles in various developmental contexts. Multiple mechanisms are involved in the regulation of Notch pathway activity. Identified through a genetic mosaic screen, we show that the ATPase TER94 acts as a positive regulator of Notch signaling during Drosophila wing development. Depletion of TER94 causes marginal notches in the adult wing and the reduction of Notch target genes wingless and cut during wing margin formation. We provide evidence that TER94 is likely required for proper Notch protein localization and activation. Furthermore, we show that knockdown of the TER94 adaptor p47 leads to similar Notch signaling defects. Although the TER94 complex is implicated in various cellular processes, its role in the regulation of Notch pathways was previously uncharacterized. Our study demonstrates that TER94 positively regulates Notch signaling and thus reveals a novel role of TER94 in development.This article has an associated First Person interview with the first author of the paper.
Highlights
The Notch signaling pathway plays important roles in tissue development and homeostasis by regulating multiple biological processes such as cell fate determination, cell proliferation and cell cycle progression (Bray, 2006)
As the ‘nicked wing margin’ represents the classical phenotype associated with dysregulation of Notch signaling, we further investigated whether Notch signaling activity is affected in TER94k15502 mutant cells
Drosophila TER94 acts broadly to regulate the activity of Hh, Wg and Bone morphogenetic protein (BMP) signaling pathways (Zhang et al, 2013; Reim et al, 2014), our report is the first to establish a functional interaction between TER94 and Notch activity during wing development
Summary
The Notch signaling pathway plays important roles in tissue development and homeostasis by regulating multiple biological processes such as cell fate determination, cell proliferation and cell cycle progression (Bray, 2006). Given the importance of Notch signaling in various cell types, it is unsurprising that aberrant Notch signaling in humans leads to many malignant diseases, such as cancers and neurological disorders (Alberi et al, 2013; Aster et al, 2017). Upon binding to its ligands Delta (Dl) and/or Serrate, the Notch receptor undergoes a series of proteolytic cleavages which results in the generation of the Notch intracellular domain (NICD) (Guruharsha et al, 2012). The NICD translocates into the nucleus, where it associates with the transcription factor Suppressor of Hairless [Su(H)] and the co-activator Mastermind to stimulate the expression of downstream target genes (Bray, 2006). In the absence of active NICD, Su(H) recruits transcription suppressors to inhibit Notch
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