Nuclear receptors linking physiology and germline stem cells in Drosophila

Abstract

Maternal nutrition and physiology are intimately associated with reproductive success in diverse organisms. Despite decades of study, the molecular mechanisms linking maternal diet to the production and quality of oocytes remain poorly defined. Nuclear receptors (NRs) link nutritional signals to cellular responses and are essential for oocyte development. The fruit fly, Drosophila melanogaster, is an excellent genetically tractable model to study the relationship between NR signaling and oocyte production. In this review, we explore how NRs in Drosophila regulate the earliest stages of oocyte development. Long-recognized as an essential mediator of developmental transitions, we focus on the intrinsic roles of the Ecdysone Receptor and its ligand, ecdysone, in oogenesis. We also review recent studies suggesting broader roles for NRs as regulators of maternal physiology and their impact specifically on oocyte production. We propose that NRs form the molecular basis of a broad physiological surveillance network linking maternal diet with oocyte production. Given the functional conservation between Drosophila and humans, continued experimental investigation into the molecular mechanisms by which NRs promote oogenesis will likely aid our understanding of human fertility.

Keywords: Drosophila; EcR; Ecdysone; Eip74EF; Eip75B; Eip78C; Germ cell; Nuclear hormone receptor; Oocyte; Oogenesis; Steroid hormone; Usp.

Fig. 1

Ecdysone signaling regulates Drosophila melanogaster oogenesis. (A) Maximum intensity projection image of a Drosophila ovariole, labeled with anti-Vasa (green; germ cells), anti-Hts (red; fusomes and follicle cell membranes), anti-LamC (red; nuclear envelope of cap cells) and DAPI (blue, DNA). (B) Optical cross section of the Drosophila germarium showing GSCs (solid white line) anchored to cap cells (dashed pink line), which make up the GSC niche. Germ cells are characterized by the presence of a fusome (orange), which extends as germ cells divide. Escort cells (yellow dashed line) signal to GSCs to promote differentiation. Follicle stem cells (FSC; purple dashed line) create pre-follicle cells that surround the 16-cell cyst, giving rise to an egg chamber or follicle that leaves the germarium. (C) Schematic of the ecdysone signaling pathway. (D) Summary of ecdysone-regulated processes in the ovariole and germarium. Scale bar = 10μm.

Fig. 2

Signaling pathways that intrinsically regulate GSC self-renewal and cystoblast differentiation. Ecdysone levels are increased due to sex peptide, which is deposited during mating and made in later stage follicles. Ecdysone is received in cap cells (pink) and GSCs (dark green). Terminal filament cells (purple) secrete the ligand Unpaired (Upd) to cap cells to stimulate the Jak/Stat pathway. The Jak/Stat pathway and ecdysone signaling regulate BMP signaling. EcR/Usp binds to Tai to control cap cell function. EcR regulates the BMP signaling pathway to regulate GSC self-renewal. The BMP ligands Gbb and Dpp are secreted from cap cells to the receptors on GSCs. This phosphorylates Mad, which will dimerize with Med and repress bam transcription. Ecdysone targets are intrinsically required to maintain GSC self-renewal. In differentiating CBs (light green) bam is transcribed and represses E-cadherin and Nos thereby committing the cell to differentiation.

Fig. 3

Ecdysone is required in somatic cells for early germline processes. In the escort cells (yellow), EcR binds to the co-activator Tai to regulate GSC (dark green) self-renewal. Ecdysone functions in a feedback loop with the miRNA let-7 and the repressor Abrupt. Ecdysone regulates the monoubiquitination of the histone H2B (H2Bub1) modification which allows for cysts (light green) to differentiate. Ecdysone signaling in the FSCs (dark purple) and follicle cells (light purple) drives formation and encapsulation of 16 cell cysts.

Fig. 4

Follicle cell polarity in mid-stages is driven by ecdysone signaling. EcR-B1 regulates F-actin (maroon) expression, and localization of the adherens junction proteins Arm and E-Cad (red), the septate junction proteins Dlg and Scrib (gray), and aPKC (blue), in mid-stage follicle cells (purple).

Fig. 5

Ecdysone signaling regulates the timing of border cell movement. Upd ligand in polar cells (orange) establishes future border cells (blue) from follicle cells (light purple). In stage 8 follicles, Abrupt binds Tai and prevents its binding to EcR. This blocks turnover of the cohesion proteins E-cadherin and β-catenin (arm). In stage 9 border cells, ecdysone inhibits Abrupt, allowing Tai to bind to EcR. Tai/EcR creates turnover of E-cadherin and β-catenin, promoting border cell migration.