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

Abstract

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 alternating 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 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 a group of transcriptional co-activators in vertebrates known as PGC-1. 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 of Spargel in the Drosophila larval salivary gland, which influences E2F1-mediated cellular growth. To elucidate the role of Spargel in the salivary gland, we performed FLP/FRT-mediated clonal analysis and found that a cell-specific loss of Spargel leads to smaller nuclei with reduced DNA content due to the early termination of DNA replication. Further, the selective absence of Spargel abrogates the expression of a key DNA replication factor called E2F1, which promotes G1[->]S transition in endocycle. Thus, mechanistically, Spargel plays a key role in cell growth by positively influencing the endocycle process through the E2F1 pathway.