title: Oocyte-dependent activation of MTOR in cumulus cells controls the development and survival of cumulus-oocyte complexes.
abstract: Communication between oocytes and their companion somatic cells promotes the healthy development of ovarian follicles, which is crucial for producing oocytes that can be fertilized and are competent to support embryogenesis. However, how oocyte-derived signaling regulates these essential processes remains largely undefined. Here, we demonstrate that oocyte-derived paracrine factors, particularly GDF9 and GDF9-BMP15 heterodimer, promote the development and survival of cumulus-cell-oocyte complexes (COCs), partly by suppressing the expression of Ddit4l, a negative regulator of MTOR, and enabling the activation of MTOR signaling in cumulus cells. Cumulus cells expressed less Ddit4l mRNA and protein than mural granulosa cells, which is in striking contrast to the expression of phosphorylated RPS6 (a major downstream effector of MTOR). Knockdown of Ddit4l activated MTOR signaling in cumulus cells, whereas inhibition of MTOR in COCs compromised oocyte developmental competence and cumulus cell survival, with the latter likely to be attributable to specific changes in a subset of transcripts in the transcriptome of COCs. Therefore, oocyte suppression of Ddit4l expression allows for MTOR activation in cumulus cells, and this oocyte-dependent activation of MTOR signaling in cumulus cells controls the development and survival of COCs.
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, People's Republic of China.
authors.forename: Jing
authors.identifier: 0000-0002-2595-7314
authors.initials: J
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, People's Republic of China.
authors.forename: Lanying
authors.identifier: 0000-0002-2761-0787
authors.initials: L
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, People's Republic of China.
authors.forename: Xuhong
authors.identifier: 0000-0001-6650-0903
authors.initials: X
authors.lastname: Gong
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, People's Republic of China.
authors.forename: Mengjie
authors.identifier: 0000-0002-2720-7517
authors.initials: M
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, People's Republic of China.
authors.forename: Yaoxue
authors.identifier: 0000-0003-0098-3425
authors.initials: Y
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, People's Republic of China.
authors.forename: Xiaoyun
authors.identifier: 0000-0002-9496-8041
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, People's Republic of China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, People's Republic of China.
authors.forename: Hui
authors.identifier: 0000-0001-5593-5004
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Animal Resource Sciences, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Emori
authors.affiliation: Department of Animal Resource Sciences, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Sugiura
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Eppig
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, People's Republic of China Key Laboratory of Model Animal Research, Nanjing Medical University, Nanjing, Jiangsu 211166, People's Republic of China youqiang.su@njmu.edu.cn.
authors.forename: You-Qiang
authors.identifier: 0000-0003-3537-6246
authors.initials: YQ
authors.lastname: Su
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D055430:Bone Morphogenetic Protein 15 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D054885:Cumulus Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D055785:Gene Knockdown Techniques; D055429:Growth Differentiation Factor 9 / Q000378:metabolism; D006736:Horses; D051379:Mice; D009154:Mutation / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D009865:Oocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D019899:Paracrine Communication / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D055430:Bone Morphogenetic Protein 15; D006063:Chorionic Gonadotropin; D004268:DNA-Binding Proteins; C450979:Ddit4l protein, mouse; D055429:Growth Differentiation Factor 9; D012333:RNA, Messenger; D051899:Smad2 Protein; D014157:Transcription Factors; D058570:TOR Serine-Threonine Kinases
keywords: Apoptosis; Cumulus cells; DDIT4L; Female infertility; MTOR; Oocyte