Regulation of the endocycle/gene amplification switch by Notch and ecdysone signaling

Abstract

The developmental signals that regulate the switch from genome-wide DNA replication to site-specific amplification remain largely unknown. Drosophila melanogaster epithelial follicle cells, which begin synchronized chorion gene amplification after three rounds of endocycle, provide an excellent model for study of the endocycle/gene amplification (E/A) switch. Here, we report that down-regulation of Notch signaling and activation of ecdysone receptor (EcR) are required for the E/A switch in these cells. Extended Notch activity suppresses EcR activation and prevents exit from the endocycle. Tramtrack (Ttk), a zinc-finger protein essential for the switch, is regulated negatively by Notch and positively by EcR. Ttk overexpression stops endoreplication prematurely and alleviates the endocycle exit defect caused by extended Notch activity or removal of EcR function. Our results reveal a developmental pathway that includes down-regulation of Notch, activation of the EcR, up-regulation of Ttk to execute the E/A switch, and, for the first time, the genetic interaction between Notch and ecdysone signaling in regulation of cell cycle programs and differentiation.

Steroid signaling in mature follicles is important for Drosophila ovulation

“…Because ecdysteroid secretion is mediated through a regulated vesicular trafficking mechanism (42), it is conceivable that follicle cells, nurse cells, or both could produce local pulses of ecdysteroids to promote egg chamber development at each transition during oogenesis. This hypothesis is consistent with the finding that the ligand sensor for ecdysteroids shows a stage-specific activity including stage 10 and stage 14 (32,33). This notion is further supported by this study that up-regulation of Shd in mature follicle cells produces 20E to regulate ovulation and a previous study that local ecdysteroids produced in follicle cells regulate border cell migration (37).…”

“…Our study defined the dynamic expression pattern of Shd and EcR isoforms in late oogenesis and demonstrated the requirement of ecdysteroid signaling in ovulation. Ecdysteroids have also been shown to regulate early germ cell differentiation (35,36), egg chamber progression at stage 8-9 (29)(30)(31), and endocycle-to-gene-amplification switch at stage10B (33). This temporal action of ecdysteroids is reminiscent to their roles in regulating multiple larval and pupal transitions (27,28).…”

“…Ecdysteroids have long been known to play essential roles in developmental transitions, such as larval molting and metamorphosis (27,28). In contrast, the roles of ecdysteroids in adult physiology have just started to emerge (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39).…”

A Screen for Modifiers of Notch Signaling Uncovers Amun, a Protein With a Critical Role in Sensory Organ Development

“…Ecdysteroids are hormones found only in arthropods that induce signals required for postembryonic development (Kozlova and Thummel 2000). The recovery of Hr38 as a Notch antagonist from our screen is not surprising considering that Notch signaling and EcR-mediated ecdysone signaling have recently been shown to act antagonistically in oogenesis during the switch from endoreplication (whole-genome amplification without cell division) to amplification (amplification of specific genes only, without cell division) (Sun et al 2008). These results, considered in light of the Members of a set of 274 candidate genes predicted to be affected by the 170 modifying transposons were placed within seven functional categories or classified as unknown.…”

Wg Signaling via Zw3 and Mad Restricts Self-Renewal of Sensory Organ Precursor Cells in Drosophila

“…pH3 is generally utilized to mark mitotic cells but is also expressed during endocycles of DNA replication such as those in ovarian follicle cells (Sun et al 2008). If the role of Zw3-phosphorylated Mad in the sensory organ lineage is to restrict mitosis, then MadRNAi and MGM should display more Sens or pH3 cells than the phenotypically wild-type Sca-Mad.…”