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Central to this process is the bidirectional communication between the oocyte and granulosa cells, mediated by oocyte\u2010secreted factors (OSFs), including GDF9 and BMP15. While GDF9 and BMP15 are well\u2010established regulators of oocyte and follicle development, the role of additional OSFs and their coordination with GDF9 and BMP15 remains largely unclear. Here, RSPO2 is identified as a key OSF that coordinates with the GDF9:BMP15 heterodimer to regulate granulosa cell development and enhance oocyte competence. RSPO2, primarily expressed in oocytes, interacts with GDF9:BMP15 to preserve transcriptomic integrity in preantral granulosa cells. This coordination is gene\u2010specific, exhibiting either synergistic or antagonistic effects depending on the target genes, and involves crosstalk between CTNNB1\u2010 and SMAD2\u2010dependent pathways. Conditional knockout of\n                    <jats:italic>Rspo2<\/jats:italic>\n                    in oocytes causes severe defects in granulosa cell and oocyte development, leading to subfertility and earlier reproductive lifespan termination. Transcriptomic analysis shows that RSPO2 loss disrupts key granulosa cell genes (e.g.,\n                    <jats:italic>Amh, Ccnd2, Inhbb, Kitl<\/jats:italic>\n                    ) and compromises oocyte mitochondrial function, reducing developmental competence. These findings establish RSPO2 as an essential factor in the oocyte\u2010granulosa cell regulatory loop, crucial for ovarian function and fertility.\n                  <\/jats:p>","DOI":"10.1002\/advs.202501973","type":"journal-article","created":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T06:44:47Z","timestamp":1749537887000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["RSPO2 Coordinates with GDF9:BMP15 Heterodimers to Promote Granulosa Cell and Oocyte Development in Mice"],"prefix":"10.1002","volume":"12","author":[{"given":"Yingmei","family":"Wang","sequence":"first","affiliation":[{"name":"Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology School of Life Sciences Shandong University  Qingdao 266237 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjiang","family":"Li","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology School of Life Sciences Shandong University  Qingdao 266237 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liji","family":"You","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology School of Life Sciences Shandong University  Qingdao 266237 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuhui","family":"Wang","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology School of Life Sciences Shandong University  Qingdao 266237 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinglei","family":"Bie","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology School of Life Sciences Shandong University  Qingdao 266237 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyang","family":"Su","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology School of Life Sciences Shandong University  Qingdao 266237 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanying","family":"Shi","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology School of Life Sciences Shandong University  Qingdao 266237 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3537-6246","authenticated-orcid":false,"given":"You\u2010Qiang","family":"Su","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology School of Life Sciences Shandong University  Qingdao 266237 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,10]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coemr.2021.03.015"},{"key":"e_1_2_10_1_2","doi-asserted-by":"publisher","DOI":"10.21451\/1984-3143-AR2018-0061"},{"key":"e_1_2_10_1_3","doi-asserted-by":"publisher","DOI":"10.1530\/rep.0.1220829"},{"key":"e_1_2_10_1_4","doi-asserted-by":"publisher","DOI":"10.1210\/er.2014-1020"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.114.121756"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2018.02.012"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2018.02.039"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/mrd.23645"},{"key":"e_1_2_10_5_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0028-1108008"},{"key":"e_1_2_10_5_3","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22829-2"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.2001.0216"},{"key":"e_1_2_10_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmu036"},{"key":"e_1_2_10_6_3","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmv036"},{"key":"e_1_2_10_6_4","doi-asserted-by":"publisher","DOI":"10.1038\/385525a0"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/383531a0"},{"key":"e_1_2_10_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2004.08.020"},{"key":"e_1_2_10_7_3","doi-asserted-by":"publisher","DOI":"10.1210\/mend.15.6.0662"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.671487"},{"key":"e_1_2_10_8_2","first-page":"E776","volume":"110","author":"Peng J.","year":"2013","journal-title":"Proc. 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