Spargel/dPGC-1 influences cell growth through the E2F1-mediated endocycle pathway

The endocycle is a specialized variant of the eukaryotic cell cycle program observed in various tissues across diverse organisms ranging from insects to mammals. The endocycle promotes cellular growth by oscillating between the synthesis (S) and gap (G) phases, completely bypassing mitosis (M phase). E2F1 serves as a master regulator of the endocycle in Drosophila salivary glands, whereas the target of rapamycin (TOR) signaling pathway controls the levels of the E2F1 protein post-transcriptionally. Cellular growth in tissues that undergo the endocycle is also dependent on nutrient availability. Drosophila Spargel (dPGC-1) is orthologous to the PGC-1 family of transcriptional coactivators in vertebrates. In flies, Spargel influences cell growth through the insulin signaling pathway via TOR. However, the mechanisms by which Spargel regulates endocycle-mediated growth have yet to be established. Here, we report an essential role for Spargel in the Drosophila larval salivary gland that influences E2F1-mediated cellular growth. To elucidate the role of Spargel in cellular growth, we performed flippase (FLP)/FLP recombination target (FRT)-mediated mitotic clonal analysis in the salivary gland. The clonal analysis revealed that a cell-specific, complete loss of Spargel results in smaller nuclei with reduced DNA content due to inadequate DNA replication. Furthermore, the selective absence of Spargel abrogates the expression of a key DNA replication factor, E2F1, which promotes the G1 → S transition in the endocycle. Thus, mechanistically, Spargel plays a key role in cell growth by positively influencing the endocycle process through the E2F1 pathway.