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GGPP-Mediated Protein Geranylgeranylation in Oocyte Is Essential for the Establishment of Oocyte-Granulosa Cell Communication and Primary-Secondary Follicle Transition in Mouse Ovary

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      Abstract

      Folliculogenesis is a progressive and highly regulated process, which is essential to provide ova for later reproductive life, requires the bidirectional communication between the oocyte and granulosa cells. This physical connection-mediated communication conveys not only the signals from the oocyte to granulosa cells that regulate their proliferation but also metabolites from the granulosa cells to the oocyte for biosynthesis. However, the underlying mechanism of establishing this communication is largely unknown. Here, we report that oocyte geranylgeranyl diphosphate (GGPP), a metabolic intermediate involved in protein geranylgeranylation, is required to establish the oocyte-granulosa cell communication. GGPP and geranylgeranyl diphosphate synthase (Ggpps) levels in oocytes increased during early follicular development. The selective depletion of GGPP in mouse oocytes impaired the proliferation of granulosa cells, primary-secondary follicle transition and female fertility. Mechanistically, GGPP depletion inhibited Rho GTPase geranylgeranylation and its GTPase activity, which was responsible for the accumulation of cell junction proteins in the oocyte cytoplasm and the failure to maintain physical connection between oocyte and granulosa cells. GGPP ablation also blocked Rab27a geranylgeranylation, which might account for the impaired secretion of oocyte materials such as Gdf9. Moreover, GGPP administration restored the defects in oocyte-granulosa cell contact, granulosa cell proliferation and primary-secondary follicle transition in Ggpps depletion mice. Our study provides the evidence that GGPP-mediated protein geranylgeranylation contributes to the establishment of oocyte-granulosa cell communication and then regulates the primary-secondary follicle transition, a key phase of folliculogenesis essential for female reproductive function.

      Author Summary

      Folliculogenesis is a progressive and highly regulated process that requires the tight coordination of metabolism and bidirectional communication between the oocyte and granulosa cells. How this communication is established remains unclear. Here, we find that GGPP-mediated protein geranylgeranylation, a post-translational modification, is essential for the oocyte-granulosa cell communication. GGPP depletion in oocytes inhibits Rho GTPase geranylgeranylation-regulated cell adhesion and impairs Rab GTPase geranylgeranylation-directed cell secretion, which are responsible for the failure to maintain oocyte-granulosa cell communication. This communication defect is probably not able to support the proliferation of granulosa cells from one layer to multiple layers and ultimately results in the failure of the primary-secondary follicle transition and female subfertility. Our findings provide the evidence of GGPP-mediated protein geranylgeranylation involving in regulating primary-secondary follicle transition and establish a novel link between folliculogenesis and GGPP-regulated membrane dynamics.

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      Most cited references 49

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      Results of previous randomised trials have shown that interventions that lower LDL cholesterol concentrations can significantly reduce the incidence of coronary heart disease (CHD) and other major vascular events in a wide range of individuals. But each separate trial has limited power to assess particular outcomes or particular categories of participant. A prospective meta-analysis of data from 90,056 individuals in 14 randomised trials of statins was done. Weighted estimates were obtained of effects on different clinical outcomes per 1.0 mmol/L reduction in LDL cholesterol. During a mean of 5 years, there were 8186 deaths, 14,348 individuals had major vascular events, and 5103 developed cancer. Mean LDL cholesterol differences at 1 year ranged from 0.35 mmol/L to 1.77 mmol/L (mean 1.09) in these trials. There was a 12% proportional reduction in all-cause mortality per mmol/L reduction in LDL cholesterol (rate ratio [RR] 0.88, 95% CI 0.84-0.91; p<0.0001). This reflected a 19% reduction in coronary mortality (0.81, 0.76-0.85; p<0.0001), and non-significant reductions in non-coronary vascular mortality (0.93, 0.83-1.03; p=0.2) and non-vascular mortality (0.95, 0.90-1.01; p=0.1). There were corresponding reductions in myocardial infarction or coronary death (0.77, 0.74-0.80; p<0.0001), in the need for coronary revascularisation (0.76, 0.73-0.80; p<0.0001), in fatal or non-fatal stroke (0.83, 0.78-0.88; p<0.0001), and, combining these, of 21% in any such major vascular event (0.79, 0.77-0.81; p<0.0001). The proportional reduction in major vascular events differed significantly (p<0.0001) according to the absolute reduction in LDL cholesterol achieved, but not otherwise. These benefits were significant within the first year, but were greater in subsequent years. Taking all years together, the overall reduction of about one fifth per mmol/L LDL cholesterol reduction translated into 48 (95% CI 39-57) fewer participants having major vascular events per 1000 among those with pre-existing CHD at baseline, compared with 25 (19-31) per 1000 among participants with no such history. There was no evidence that statins increased the incidence of cancer overall (1.00, 0.95-1.06; p=0.9) or at any particular site. Statin therapy can safely reduce the 5-year incidence of major coronary events, coronary revascularisation, and stroke by about one fifth per mmol/L reduction in LDL cholesterol, largely irrespective of the initial lipid profile or other presenting characteristics. The absolute benefit relates chiefly to an individual's absolute risk of such events and to the absolute reduction in LDL cholesterol achieved. These findings reinforce the need to consider prolonged statin treatment with substantial LDL cholesterol reductions in all patients at high risk of any type of major vascular event.
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        The mevalonate pathway produces isoprenoids that are vital for diverse cellular functions, ranging from cholesterol synthesis to growth control. Several mechanisms for feedback regulation of low-density-lipoprotein receptors and of two enzymes involved in mevalonate biosynthesis ensure the production of sufficient mevalonate for several end-products. Manipulation of this regulatory system could be useful in treating certain forms of cancer as well as heart disease.
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          Rab27a and Rab27b control different steps of the exosome secretion pathway.

          Exosomes are secreted membrane vesicles that share structural and biochemical characteristics with intraluminal vesicles of multivesicular endosomes (MVEs). Exosomes could be involved in intercellular communication and in the pathogenesis of infectious and degenerative diseases. The molecular mechanisms of exosome biogenesis and secretion are, however, poorly understood. Using an RNA interference (RNAi) screen, we identified five Rab GTPases that promote exosome secretion in HeLa cells. Among these, Rab27a and Rab27b were found to function in MVE docking at the plasma membrane. The size of MVEs was strongly increased by Rab27a silencing, whereas MVEs were redistributed towards the perinuclear region upon Rab27b silencing. Thus, the two Rab27 isoforms have different roles in the exosomal pathway. In addition, silencing two known Rab27 effectors, Slp4 (also known as SYTL4, synaptotagmin-like 4) and Slac2b (also known as EXPH5, exophilin 5), inhibited exosome secretion and phenocopied silencing of Rab27a and Rab27b, respectively. Our results therefore strengthen the link between MVEs and exosomes, and introduce ways of manipulating exosome secretion in vivo.
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            Author and article information

            Affiliations
            [1 ]MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center and School of Medicine, Nanjing University, National Resource Centre for Mutant Mice, Nanjing, China
            [2 ]Collaborative Innovation Platform for Reproductive Biology and Technology of the Medical School of Nanjing University, Nanjing, China
            [3 ]School of Life Science and Technology, Shanghai Tech University, Shanghai, China
            Syracuse University, UNITED STATES
            Author notes

            The authors have declared that no competing interests exist.

            • Conceptualization: CJ CJL.

            • Data curation: CJ CJL.

            • Formal analysis: CJ FD.

            • Funding acquisition: CJL.

            • Investigation: CJ FD YJS NX RLZ XXW ZC WWT.

            • Methodology: CJ FD.

            • Project administration: CJ CJL.

            • Resources: CJ BY HXS XXH BX CJL.

            • Supervision: CJ CJL.

            • Validation: CJ FD CJL.

            • Visualization: CJ CJL.

            • Writing – original draft: CJ CJL.

            • Writing – review & editing: CJ CJL.

            Contributors
            Role: Editor
            Journal
            PLoS Genet
            PLoS Genet
            plos
            plosgen
            PLoS Genetics
            Public Library of Science (San Francisco, CA USA )
            1553-7390
            1553-7404
            10 January 2017
            January 2017
            : 13
            : 1
            28072828
            5224981
            10.1371/journal.pgen.1006535
            PGENETICS-D-16-01051
            (Editor)
            © 2017 Jiang et al

            This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

            Counts
            Figures: 7, Tables: 0, Pages: 19
            Product
            Funding
            Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
            Award ID: 31530046
            Award Recipient :
            This work was supported by the National Natural Science Foundation of China (Grant No. 31530046 and No. 31271540, http://www.nsfc.gov.cn, to CJL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
            Categories
            Research Article
            Biology and Life Sciences
            Cell Biology
            Cellular Types
            Animal Cells
            Germ Cells
            OVA
            Oocytes
            Biology and Life Sciences
            Anatomy
            Reproductive System
            Ovaries
            Medicine and Health Sciences
            Anatomy
            Reproductive System
            Ovaries
            Biology and Life Sciences
            Cell Biology
            Cellular Types
            Animal Cells
            Epithelial Cells
            Granulosa Cells
            Biology and Life Sciences
            Anatomy
            Biological Tissue
            Epithelium
            Epithelial Cells
            Granulosa Cells
            Medicine and Health Sciences
            Anatomy
            Biological Tissue
            Epithelium
            Epithelial Cells
            Granulosa Cells
            Biology and Life Sciences
            Cell Biology
            Cellular Types
            Animal Cells
            Lutein Cells
            Granulosa Cells
            Biology and Life Sciences
            Biochemistry
            Enzymology
            Enzymes
            Hydrolases
            Guanosine Triphosphatase
            Biology and Life Sciences
            Biochemistry
            Proteins
            Enzymes
            Hydrolases
            Guanosine Triphosphatase
            Biology and Life Sciences
            Cell Biology
            Cell Physiology
            Cell Communication
            Biology and Life Sciences
            Cell Biology
            Cellular Structures and Organelles
            Cell Membranes
            Biology and Life Sciences
            Biochemistry
            Metabolism
            Protein Metabolism
            Research and Analysis Methods
            Immunologic Techniques
            Immunoassays
            Immunofluorescence
            Custom metadata
            All relevant data are within the paper and its Supporting Information files.

            Genetics

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