Browsing by Subject "FoxO"

The roundworm C. elegans reversibly arrests larval development during starvation, but extended early-life starvation reduces reproductive success. Maternal dietary restriction (DR) buffers progeny from starvation as young larvae, preserving reproductive success. However, the developmental basis of reduced fertility following early-life starvation is unknown, and it is unclear how maternal diet modifies developmental physiology in progeny. We show here that extended starvation in first-stage (L1) larvae followed by unrestricted feeding results in a variety of developmental abnormalities in the reproductive system, including proliferative germ-cell tumors and uterine masses that express neuronal and epidermal cell-fate markers. We found that maternal DR and reduced maternal insulin/IGF signaling (IIS) increase oocyte provisioning of vitellogenin lipoprotein, reducing penetrance of starvation-induced abnormalities in progeny, including tumors. Furthermore, we show that maternal DR and reduced maternal IIS reduce IIS in progeny. daf-16/FoxO and skn-1/Nrf, transcriptional effectors of IIS, are required in progeny for maternal DR and increased vitellogenin provisioning to suppress starvation-induced abnormalities. daf-16/FoxO activity in somatic tissues is sufficient to suppress starvation-induced abnormalities, suggesting cell-nonautonomous regulation of reproductive system development. This work reveals that early-life starvation compromises reproductive development and that vitellogenin-mediated intergenerational insulin/IGF-to-insulin/IGF signaling mediates adaptation to nutrient availability. Using our SIA model, we go on to show that early-life starvation persistently activates PQM-1/SALL2 with pervasive effects on adult gene expression, including prominent effects on membrane biology. Early-life starvation increases fatty-acid synthetase fasn-1/FASN expression in pqm-1/SALL2-dependent fashion, and both genes promote SIA. Lipidomic analysis implicates phosphatidylcholine, and unsaturated phosphatidylcholine supplementation suppresses SIA. The fatty-acid desaturases fat-1 and fat-4 inhibit and promote SIA, respectively, revealing a role of arachidonic acid-containing phosphatidylcholine, the Lands cycle, and eicosanoid signaling. Indeed, fat-4 increases eicosanoid levels in adults subjected to early-life starvation, and N-acetylcysteine treatment suppresses SIA. This work shows that early-life starvation and IIS converge on PQM-1/SALL2 to affect adult lipid metabolism and eicosanoid signaling, affecting stem-cell proliferation and tumor formation.