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Discovery of two GLP-1/Notch target genes that account for the role of GLP-1/Notch signaling in stem cell maintenance

Significance Stem cells generate tissues, and they can be hijacked in cancer. A fundamental mechanism of stem cell regulation is signaling from their immediate microenvironment, or niche. Although many niches and signaling pathways have been identified, much less is known about how stem cells respond. Here, we report the discovery of two key niche signaling effector genes. These genes are activated in stem cells by Notch signaling, a conserved and clinically significant pathway, and together are essential for the stem cell state. Surprisingly, neither was previously implicated in stem cell regulation and their sequences yield few clues to their functions. We suggest that these newly discovered genes may be pioneers for a new class of stem cell regulators. A stem cell’s immediate microenvironment creates an essential “niche” to maintain stem cell self-renewal. Many niches and their intercellular signaling pathways are known, but for the most part, the key downstream targets of niche signaling remain elusive. Here, we report the discovery of two GLP-1/Notch target genes, lst-1 (lateral signaling target) and sygl-1 (synthetic Glp), that function redundantly to maintain germ-line stem cells (GSCs) in the nematode Caenorhabditis elegans. Whereas lst-1 and sygl-1 single mutants appear normal, lst-1 sygl-1 double mutants are phenotypically indistinguishable from glp-1/Notch mutants. Multiple lines of evidence demonstrate that GLP-1/Notch signaling activates lst-1 and sygl-1 expression in GSCs within the niche. Therefore, these two genes fully account for the role of GLP-1/Notch signaling in GSC maintenance. Importantly, lst-1 and sygl-1 are not required for GLP-1/Notch signaling per se. We conclude that lst-1 and sygl-1 forge a critical link between Notch signaling and GSC maintenance.