Abstract
ABSTRACTThe Notch signalling pathway is a conserved and widespread signalling paradigm, and its misregulation has been implicated in numerous disorders, including cancer. The output of Notch signalling depends on the nuclear accumulation of the Notch receptor intracellular domain (ICD). Using the Caenorhabditis elegans germline, where GLP-1/Notch-mediated signalling is essential for maintaining stem cells, we monitored GLP-1 in vivo. We found that the nuclear enrichment of GLP-1 ICD is dynamic: while the ICD is enriched in germ cell nuclei during larval development, it is depleted from the nuclei in adult germlines. We found that this pattern depends on the ubiquitin proteolytic system and the splicing machinery and, identified the splicing factor PRP-19 as a candidate E3 ubiquitin ligase required for the nuclear depletion of GLP-1 ICD.
Highlights
Notch signalling is a highly conserved communication pathway with numerous cellular and developmental roles
The nuclear localization of GLP-1 in germ cells is dynamic during development the essential function of GLP-1 signalling in promoting the self-renewal of germ cells is well established [reviewed in Kimble and Crittenden (2005, 2007)], the nuclear localization of GLP-1 has not been reported
Despite the essential proliferation-promoting role of GLP-1, the nuclear GLP-1::GFP was not observed in adults (Fig. 1C), suggesting the existence of a mechanism restricting the nuclear accumulation of GLP-1 intracellular domain (ICD) in adult gonads
Summary
Notch signalling is a highly conserved communication pathway with numerous cellular and developmental roles. Defects in Notch signalling can lead to diverse diseases, including cancer (Artavanis-Tsakonas et al, 1999; Bray, 2006). The signalling depends on the interaction between a Notch receptor and its ligand, which are expressed in neighbouring cells. Upon the binding of a DSL (Delta Serrate LAG-2 family) ligand, the Notch receptor is subjected to sequential cleavages, releasing the intracellular domain (ICD) from the cell membrane. The ICD translocates into the nucleus, where it associates with transcriptional co-activators, regulating transcription of cell type-specific target genes (Bray, 2006).
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