Abstract
The correct establishment and maintenance of unidirectional Notch signaling are critical for the homeostasis of various stem cell lineages. However, the molecular mechanisms that prevent cell-autonomous ectopic Notch signaling activation and deleterious cell fate decisions remain unclear. Here we show that the retromer complex directly and specifically regulates Notch receptor retrograde trafficking in Drosophila neuroblast lineages to ensure the unidirectional Notch signaling from neural progenitors to neuroblasts. Notch polyubiquitination mediated by E3 ubiquitin ligase Itch/Su(dx) is inherently inefficient within neural progenitors, relying on retromer-mediated trafficking to avoid aberrant endosomal accumulation of Notch and cell-autonomous signaling activation. Upon retromer dysfunction, hypo-ubiquitinated Notch accumulates in Rab7+ enlarged endosomes, where it is ectopically processed and activated in a ligand-dependent manner, causing progenitor-originated tumorigenesis. Our results therefore unveil a safeguard mechanism whereby retromer retrieves potentially harmful Notch receptors in a timely manner to prevent aberrant Notch activation-induced neural progenitor dedifferentiation and brain tumor formation.
Highlights
The correct establishment and maintenance of unidirectional Notch signaling are critical for the homeostasis of various stem cell lineages (Bertet et al, 2014; Blanpain et al, 2006; Bowman et al, 2008; Conboy and Rando, 2002; Fre et al, 2005; Guo and Ohlstein, 2015; Lin et al, 2012; Liu et al, 2017; Ohlstein and Spradling, 2007; Ren et al, 2018; Song and Lu, 2011; Williams et al, 2011)
The retromer complex prevents neural progenitor dedifferentiation and tumorigenesis To investigate the function of retromer in neuroblast lineages, we first downregulated Vps26 in all central brain neuroblast lineages using short hairpin microRNAs, driven by insc-Gal4, and observed a supernumerary neuroblast phenotype (Figure 1D,E)
The molecular mechanisms establishing the unidirectionality of Notch signaling in stem cell lineages remain unclear
Summary
The correct establishment and maintenance of unidirectional Notch signaling are critical for the homeostasis of various stem cell lineages (Bertet et al, 2014; Blanpain et al, 2006; Bowman et al, 2008; Conboy and Rando, 2002; Fre et al, 2005; Guo and Ohlstein, 2015; Lin et al, 2012; Liu et al, 2017; Ohlstein and Spradling, 2007; Ren et al, 2018; Song and Lu, 2011; Williams et al, 2011). An important strategy utilized by dividing stem cells or progenitors to ensure binary cell fate decisions is asymmetric segregation of the endocytic protein Numb, an evolutionarily conserved Notch signaling antagonist, to one of the daughter cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
