title: GGPP-Mediated Protein Geranylgeranylation in Oocyte Is Essential for the Establishment of Oocyte-Granulosa Cell Communication and Primary-Secondary Follicle Transition in Mouse Ovary.
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.
authors.affiliation: 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.|Collaborative Innovation Platform for Reproductive Biology and Technology of the Medical School of Nanjing University, Nanjing, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Jiang
authors.affiliation: 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.
authors.forename: Fan
authors.initials: F
authors.lastname: Diao
authors.affiliation: 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.|Collaborative Innovation Platform for Reproductive Biology and Technology of the Medical School of Nanjing University, Nanjing, China.
authors.forename: Yong-Juan
authors.identifier: http://orcid.org/0000-0002-7304-4392
authors.initials: YJ
authors.lastname: Sang
authors.affiliation: 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.
authors.forename: Na
authors.initials: N
authors.lastname: Xu
authors.affiliation: 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.|Collaborative Innovation Platform for Reproductive Biology and Technology of the Medical School of Nanjing University, Nanjing, China.
authors.forename: Rui-Lou
authors.initials: RL
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Xiu-Xing
authors.initials: XX
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Tao
authors.affiliation: Collaborative Innovation Platform for Reproductive Biology and Technology of the Medical School of Nanjing University, Nanjing, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Yao
authors.affiliation: Collaborative Innovation Platform for Reproductive Biology and Technology of the Medical School of Nanjing University, Nanjing, China.
authors.forename: Hai-Xiang
authors.initials: HX
authors.lastname: Sun
authors.affiliation: School of Life Science and Technology, Shanghai Tech University, Shanghai, China.
authors.forename: Xing-Xu
authors.initials: XX
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Bin
authors.initials: B
authors.lastname: Xue
authors.affiliation: 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.|Collaborative Innovation Platform for Reproductive Biology and Technology of the Medical School of Nanjing University, Nanjing, China.
authors.forename: Chao-Jun
authors.initials: CJ
authors.lastname: Li
mesh_terms: D000818:Animals; D002450:Cell Communication; D002478:Cells, Cultured; D051231:Farnesyltranstransferase / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006107:Granulosa Cells / Q000378:metabolism*; D055429:Growth Differentiation Factor 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism*; D006080:Ovarian Follicle / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000075745:rab27 GTP-Binding Proteins
chemical_list: C525898:Gdf9 protein, mouse; C495428:Ggps1 protein, mouse; D055429:Growth Differentiation Factor 9; D009097:Multienzyme Complexes; D011106:Polyisoprenyl Phosphates; D000075745:rab27 GTP-Binding Proteins; D051231:Farnesyltranstransferase; C512962:Rab27a protein, mouse; D020691:rab GTP-Binding Proteins; C002963:geranylgeranyl pyrophosphate