# An insulin receptor activity surge in follicle cells drives vitellogenesis by upregulating CrebA

## TL;DR

Insulin signaling in fruit fly follicle cells boosts yolk production through a protein called CrebA, and this mechanism is conserved in human cells.

## Contribution

The study identifies a conserved regulatory axis involving insulin signaling, CrebA, and FoxO in follicle cells across species.

## Key findings

- Insulin receptor activity surges in Drosophila follicle cells during vitellogenesis.
- CrebA activates genes for yolk and membrane proteins, and its expression is suppressed by FoxO under insulin disruption or high-sucrose diets.
- The FOXO1-CREB3L2 module in human granulosa cells mirrors the Drosophila regulatory mechanism.

## Abstract

Folliculogenesis is a process that requires accurate interpretation of female physiological cues and elaborate coordination between the growing oocyte and its surrounding follicle cells, each being capable of responding to external signals. Here, we investigate the role of insulin signaling in Drosophila follicle cells. Using a phase separation-based reporter system, we observe a surge of insulin receptor activity in follicle cells during vitellogenic stages, a surge that is disrupted by a maternal high-sucrose diet. Single-cell RNA-seq reveals a diet-sensitive subpopulation of stage-8 follicle cells, which exhibits a reduction in CrebA-mediated transcription of genes for yolk and vitelline membrane proteins. Our results suggest a critical role of CrebA in implementing the stage-specific effect of insulin signaling to boost the secretory capacity of follicle cells. Mechanistically, CrebA is directly repressed by nuclear FoxO that is subject to insulin control, a regulatory axis that we show is conserved in human granulosa cells. This study delineates a mechanism through which insulin and nutrient cues act on a developmental transition via modulating the biosynthetic and secretory functions of the ovary.

Drosophila ovarian follicle cells undergo a surge of insulin receptor activity required for vitellogenesis and successful oogenesis. CrebA has a critical role in implementing this stage-specific effect of insulin signaling to increase the secretory capacity of follicle cells.

Insulin receptor activity in Drosophila follicle cells exhibits a temporary surge during vitellogenesis.CrebA transcriptionally activates yolk and vitelline membrane proteins in vitellogenic follicle cells.Insulin receptor activity loss or high-sucrose diet suppresses CrebA expression through an increased FoxO activity.The FOXO1-CREB3L2 regulatory module is the human counterpart in granulosa cells.

Insulin receptor activity in Drosophila follicle cells exhibits a temporary surge during vitellogenesis.

CrebA transcriptionally activates yolk and vitelline membrane proteins in vitellogenic follicle cells.

Insulin receptor activity loss or high-sucrose diet suppresses CrebA expression through an increased FoxO activity.

The FOXO1-CREB3L2 regulatory module is the human counterpart in granulosa cells.

Drosophila ovarian follicle cells undergo a surge of insulin receptor activity required for vitellogenesis and successful oogenesis. CrebA has a critical role in implementing this stage-specific effect of insulin signaling to increase the secretory capacity of follicle cells.