UNC-6 compensate for the loss-of DCC/UNC-40 in regulating C. elegans germ cell apoptosis, depending on the presence of Netrin-1/UNC-6

Abstract Oogenesis is an energy-intensive process critical for reproductive success. To ensure proper coordination with developmental stages and nutritional status, complex regulatory mechanisms have evolved. Using C. elegans previous studies have emphasized the role of hypodermis and intestinal cells—key tissues that sense developmental status and environmental nutrition—as major regulators of oogenesis and reproduction, while whether and how neurons also play a role in regulating oogenesis is not well studied. In this study, we found that a neuron derived signaling pathway, Netrin-1/UNC-6 and its receptors DCC/UNC-40 and UNC-5 regulates germ cell apoptosis. Our results indicate that Deleted in Colorectal Cancer, DCC/UNC-40 differently regulate germ cell apoptosis depending on the presence of its ligand Netrin-1/UNC-6. Loss-of DCC/UNC-40 promotes apoptosis in the presence of Netrin-1/UNC-6, while inhibits apoptosis in the absence of Netrin-1/UNC-6. The alternative receptor of Netrin-1/UNC-6, UNC-5 compensates for the loss-of DCC/UNC-40, and partially explains for the opposite effect of DCC/UNC-40 in regulating apoptosis, dependent on its ligand Netrin-1/UNC-6. Our results revealed a potential compensation mechanism of the controversial function of DCC/UNC-40 on regulating apoptosis, as well as colorectal cancer development, and thus provided a potential therapy for colorectal cancer by synthetically targeting DCC/UNC-40 with its ligand Netrin-1/UNC-6, or with its competitive Netrin-1/UNC-6 receptor UNC-5.