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Downregulation of homeodomain protein Cut is essential for Drosophila follicle maturation and ovulation.

ABSTRACT: Proper development and maturation of a follicle is essential for successful ovulation and reproduction; however, the molecular mechanisms for follicle maturation, particularly for somatic follicle cell differentiation, are poorly understood. During Drosophila oogenesis, the somatic follicle cells encasing oocytes undergo two distinct well-established transitions: the mitotic to endocycle switch at stage 6/7 and the endocycle to gene amplification switch at stage10A/10B. Here, we identify a novel third follicle cell transition that occurs in the final stages of oogenesis (stage 13/14). This late follicle cell transition is characterized by upregulation of the transcription factor Hindsight (Hnt), and downregulation of the homeodomain transcription factor Cut and the zinc-finger transcription factor Tramtrack-69 (Ttk69). We demonstrate that inducing expression of Cut in stage 14 follicle cells is sufficient to inhibit follicle rupture and ovulation through its negative regulation of Hnt and promotion of Ttk69 expression. Our work illustrates the importance of the stage13/14 transition for follicle maturation and demonstrates the complex regulation required for somatic follicle cells to differentiate into a state primed for follicle rupture and ovulation.

SUBMITTER: Knapp EM

PROVIDER: S-EPMC6765176 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Downregulation of homeodomain protein Cut is essential for <i>Drosophila</i> follicle maturation and ovulation.

Knapp Elizabeth M EM Li Wei W Sun Jianjun J

Development (Cambridge, England) 20190919 18

Proper development and maturation of a follicle is essential for successful ovulation and reproduction; however, the molecular mechanisms for follicle maturation, particularly for somatic follicle cell differentiation, are poorly understood. During <i>Drosophila</i> oogenesis, the somatic follicle cells encasing oocytes undergo two distinct well-established transitions: the mitotic to endocycle switch at stage 6/7 and the endocycle to gene amplification switch at stage10A/10B. Here, we identify ...[more]

PMID: 31444217

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Project description:BackgroundCyanobacterial harmful algal blooms (CyanoHABs) originate from the excessive growth or bloom of cyanobacteria often referred to as blue-green algae. They have been on the rise globally in both marine and freshwaters in recently years with increasing frequency and severity owing to the rising temperature associated with climate change and increasing anthropogenic eutrophication from agricultural runoff and urbanization. Humans are at a great risk of exposure to toxins released from CyanoHABs through drinking water, food, and recreational activities, making CyanoHAB toxins a new class of contaminants of emerging concern.ObjectivesWe investigated the toxic effects and mechanisms of microcystin-LR (MC-LR), the most prevalent CyanoHAB toxin, on the ovary and associated reproductive functions.MethodsMouse models with either chronic daily oral or acute intraperitoneal exposure, an engineered three-dimensional ovarian follicle culture system, and human primary ovarian granulosa cells were tested with MC-LR of various dose levels. Single-follicle RNA sequencing, reverse transcription-quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting, immunohistochemistry (IHC), and benchmark dose modeling were used to examine the effects of MC-LR on follicle maturation, hormone secretion, ovulation, and luteinization.ResultsMice exposed long term to low-dose MC-LR did not exhibit any differences in the kinetics of folliculogenesis, but they had significantly fewer corpora lutea compared with control mice. Superovulation models further showed that mice exposed to MC-LR during the follicle maturation window had significantly fewer ovulated oocytes. IHC results revealed ovarian distribution of MC-LR, and mice exposed to MC-LR had significantly lower expression of key follicle maturation mediators. Mechanistically, in both murine and human granulosa cells exposed to MC-LR, there was reduced protein phosphatase 1 (PP1) activity, disrupted PP1-mediated PI3K/AKT/FOXO1 signaling, and less expression of follicle maturation-related genes.DiscussionUsing both in vivo and in vitro murine and human model systems, we provide data suggesting that environmentally relevant exposure to the CyanoHAB toxin MC-LR interfered with gonadotropin-dependent follicle maturation and ovulation. We conclude that MC-LR may pose a nonnegligible risk to women's reproductive health by heightening the probability of irregular menstrual cycles and infertility related to ovulatory disorders. https://doi.org/10.1289/EHP12034.

Dataset Information

Downregulation of homeodomain protein Cut is essential for Drosophila follicle maturation and ovulation.

Publications

Downregulation of homeodomain protein Cut is essential for <i>Drosophila</i> follicle maturation and ovulation.

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