{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T10:16:00Z","timestamp":1791108960433,"version":"4.1.0"},"reference-count":44,"publisher":"The Company of Biologists","issue":"22","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2005,11,15]]},"abstract":"<jats:p>Paracrine factors secreted by the oocyte regulate a broad range of cumulus cell functions. Characteristically, cumulus cells have a low incidence of apoptosis and we proposed that this is due to oocyte-secreted factors acting in an anti-apoptotic manner. Bovine cumulus-oocyte complexes (COC) were aspirated from abattoir-derived ovaries and oocytectomized (OOX) by microsurgical removal of the oocyte. OOX were treated with doses of either denuded oocytes (DO) or various growth factors for 24 hours (\u00b1 rFSH; 0.1 IU\/ml). Proportions of apoptotic cumulus cells were assessed using TUNEL and laser confocal scanning microscopy followed by image analysis. Quantification of Bcl-2 and Bax proteins in OOX was undertaken by western analysis. Oocyte removal led to a significant increase in cumulus cell apoptosis compared with COC controls (35% versus 9% TUNEL positive, respectively; P&amp;lt;0.001). Levels of OOX apoptosis were significantly reversed (P&amp;lt;0.001) in a dose-dependent manner when co-cultured with oocytes. Furthermore, the anti-apoptotic effect of oocyte-secreted factors followed a gradient from the site of the oocyte(s). Growth differentiation factor 9 (GDF9) had no significant effect on cumulus cell apoptosis. By contrast, cumulus cell apoptosis was significantly (P&amp;lt;0.001) reduced by bone morphogenetic proteins (BMP) 15, 6 or 7. Accordingly, levels of anti-apoptotic Bcl-2 were high in OOX+DO and OOX+BMP15 and low with OOX+GDF9 or OOX alone, whereas the reverse was observed for pro-apoptotic Bax. DO, BMP15 and BMP6 were also able to protect cumulus cells from undergoing apoptosis induced by staurosporine. FSH partially prevented apoptosis in all treatment groups (P&amp;lt;0.001). Follistatin and a BMP6 neutralizing antibody, which antagonized the anti-apoptotic effects of BMP15 and BMP6, respectively, whether alone or combined, blocked \u223c50% of the anti-apoptotic actions of oocytes. These results are the first to demonstrate that oocyte-secreted factors, and particularly BMP15 and BMP6, maintain the low incidence of cumulus cell apoptosis by establishing a localized gradient of bone morphogenetic proteins.<\/jats:p>","DOI":"10.1242\/jcs.02644","type":"journal-article","created":{"date-parts":[[2005,11,1]],"date-time":"2005-11-01T20:23:46Z","timestamp":1130876626000},"page":"5257-5268","source":"Crossref","is-referenced-by-count":287,"title":["Oocytes prevent cumulus cell apoptosis by maintaining a morphogenic paracrine gradient of bone morphogenetic proteins"],"prefix":"10.1242","volume":"118","author":[{"given":"Tamer S.","family":"Hussein","sequence":"first","affiliation":[{"name":"Research Centre for Reproductive Health, Department of Obstetrics and Gynaecology, The University of Adelaide, The Queen Elizabeth Hospital, Woodville Road, Woodville, South Australia, 5011, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Froiland","sequence":"additional","affiliation":[{"name":"Research Centre for Reproductive Health, Department of Obstetrics and Gynaecology, The University of Adelaide, The Queen Elizabeth Hospital, Woodville Road, Woodville, South Australia, 5011, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fred","family":"Amato","sequence":"additional","affiliation":[{"name":"Research Centre for Reproductive Health, Department of Obstetrics and Gynaecology, The University of Adelaide, The Queen Elizabeth Hospital, Woodville Road, Woodville, South Australia, 5011, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy G.","family":"Thompson","sequence":"additional","affiliation":[{"name":"Research Centre for Reproductive Health, Department of Obstetrics and Gynaecology, The University of Adelaide, The Queen Elizabeth Hospital, Woodville Road, Woodville, South Australia, 5011, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert B.","family":"Gilchrist","sequence":"additional","affiliation":[{"name":"Research Centre for Reproductive Health, Department of Obstetrics and Gynaecology, The University of Adelaide, The Queen Elizabeth Hospital, Woodville Road, Woodville, South Australia, 5011, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042519094560100_REF1","doi-asserted-by":"crossref","unstructured":"Albertini, D. F., Combelles, C. M., Benecchi, E. and Carabatsos, M. J. (2001). Cellular basis for paracrine regulation of ovarian follicle development. Reproduction121, 647-653.","DOI":"10.1530\/rep.0.1210647"},{"key":"2021042519094560100_REF2","doi-asserted-by":"crossref","unstructured":"Balemans, W. and Van Hul, W. (2002). Extracellular regulation of BMP signaling in vertebrates: a cocktail of modulators. Dev. Biol.250, 231-250.","DOI":"10.1006\/dbio.2002.0779"},{"key":"2021042519094560100_REF3","doi-asserted-by":"crossref","unstructured":"Buccione, R., Vanderhyden, B. C., Caron, P. J. and Eppig, J. J. (1990). FSH-induced expansion of the mouse cumulus oophorus in vitro is dependent upon a specific factor(s) secreted by the oocyte. Dev. Biol.138, 16-25.","DOI":"10.1016\/0012-1606(90)90172-F"},{"key":"2021042519094560100_REF4","doi-asserted-by":"crossref","unstructured":"Canalis, E., Economides, A. N. and Gazzerro, E. (2003). Bone morphogenetic proteins, their antagonists, and the skeleton. Endocr. Rev.24, 218-235.","DOI":"10.1210\/er.2002-0023"},{"key":"2021042519094560100_REF5","doi-asserted-by":"crossref","unstructured":"Chun, S. Y., Billig, H., Tilly, J. L., Furuta, I., Tsafriri, A. and Hsueh, A. J. (1994). Gonadotropin suppression of apoptosis in cultured preovulatory follicles: mediatory role of endogenous insulin-like growth factor I. Endocrinology135, 1845-1853.","DOI":"10.1210\/endo.135.5.7525255"},{"key":"2021042519094560100_REF6","doi-asserted-by":"crossref","unstructured":"Chun, S. Y., Eisenhauer, K. M., Minami, S., Billig, H., Perlas, E. and Hsueh, A. J. (1996). Hormonal regulation of apoptosis in early antral follicles: follicle-stimulating hormone as a major survival factor. Endocrinology137, 1447-1456.","DOI":"10.1210\/endo.137.4.8625923"},{"key":"2021042519094560100_REF7","unstructured":"Driancourt, M. A., Fair, T. and Reynaud, K. (1998). [Oocyte apoptosis: when, how, why?]. Contracept. Fertil. Sex26, 522-527."},{"key":"2021042519094560100_REF8","doi-asserted-by":"crossref","unstructured":"Dudley, A. T., Lyons, K. M. and Robertson, E. J. (1995). A requirement for bone morphogenetic protein-7 during development of the mammalian kidney and eye. Genes Dev.9, 2795-2807.","DOI":"10.1101\/gad.9.22.2795"},{"key":"2021042519094560100_REF9","doi-asserted-by":"crossref","unstructured":"Eppig, J. J. (2001). Oocyte control of ovarian follicular development and function in mammals. Reproduction122, 829-838.","DOI":"10.1530\/rep.0.1220829"},{"key":"2021042519094560100_REF10","unstructured":"Eppig, J. J., Chesnel, F., Hirao, Y., O'Brien, M. J., Pendola, F. L., Watanabe, S. and Wigglesworth, K. (1997). Oocyte control of granulosa cell development: how and why. Hum. Reprod.12, 127-132."},{"key":"2021042519094560100_REF11","doi-asserted-by":"crossref","unstructured":"Erickson, G. F. and Shimasaki, S. (2003). The spatiotemporal expression pattern of the bone morphogenetic protein family in rat ovary cell types during the estrous cycle. Reprod. Biol. Endocrinol.1, 9.","DOI":"10.1186\/1477-7827-1-9"},{"key":"2021042519094560100_REF12","doi-asserted-by":"crossref","unstructured":"Gilchrist, R. B., Ritter, L. J. and Armstrong, D. T. (2004a). Oocyte-somatic cell interactions during follicle development in mammals. Anim. Reprod. Sci.82\/83, 431-446.","DOI":"10.1016\/j.anireprosci.2004.05.017"},{"key":"2021042519094560100_REF13","doi-asserted-by":"crossref","unstructured":"Gilchrist, R. B., Ritter, L. J., Cranfield, M., Jeffery, L. A., Amato, F., Scott, S. J., Myllymaa, S., Kaivo-Oja, N., Lankinen, H., Mottershead, D. G. et al. (2004b). Immunoneutralization of growth differentiation factor 9 reveals it partially accounts for mouse oocyte mitogenic activity. Biol. Reprod.71, 732-739.","DOI":"10.1095\/biolreprod.104.028852"},{"key":"2021042519094560100_REF14","doi-asserted-by":"crossref","unstructured":"Hardy, K. (1999). Apoptosis in the human embryo. Rev. Reprod.4, 125-134.","DOI":"10.1530\/ror.0.0040125"},{"key":"2021042519094560100_REF15","doi-asserted-by":"crossref","unstructured":"Hayashi, M., McGee, E. A., Min, G., Klein, C., Rose, U. M., van Duin, M. and Hsueh, A. J. (1999). Recombinant growth differentiation factor-9 (GDF-9) enhances growth and differentiation of cultured early ovarian follicles. Endocrinology140, 1236-1244.","DOI":"10.1210\/endo.140.3.6548"},{"key":"2021042519094560100_REF16","doi-asserted-by":"crossref","unstructured":"Hickey, T. E., Marrocco, D. L., Amato, F., Ritter, L. J., Norman, R. J., Gilchrist, R. B. and Armstrong, D. T. (2005). Androgen and oocyte-secreted factors modulate growth and differentiation porcine granulosa cell. Biol. Reprod.73, 825-832.","DOI":"10.1095\/biolreprod.104.039362"},{"key":"2021042519094560100_REF17","doi-asserted-by":"crossref","unstructured":"Irving-Rodgers, H. F., van Wezel, I. L., Mussard, M. L., Kinder, J. E. and Rodgers, R. J. (2001). Atresia revisited: two basic patterns of atresia of bovine antral follicles. Reproduction122, 761-775.","DOI":"10.1530\/rep.0.1220761"},{"key":"2021042519094560100_REF18","doi-asserted-by":"crossref","unstructured":"Jolly, P. D., Tisdall, D. J., Heath, D. A., Lun, S. and McNatty, K. P. (1994). Apoptosis in bovine granulosa cells in relation to steroid synthesis, cyclic adenosine 3\u2032,5\u2032-monophosphate response to follicle-stimulating hormone and luteinizing hormone, and follicular atresia. Biol. Reprod.51, 934-944.","DOI":"10.1095\/biolreprod51.5.934"},{"key":"2021042519094560100_REF19","doi-asserted-by":"crossref","unstructured":"Juengel, J. L. and McNatty, K. P. (2005). The role of proteins of the transforming growth factor-{beta} superfamily in the intraovarian regulation of follicular development. Hum. Reprod. Update11, 144-161.","DOI":"10.1093\/humupd\/dmh061"},{"key":"2021042519094560100_REF20","doi-asserted-by":"crossref","unstructured":"Kaivo-Oja, N., Bondestam, J., Kamarainen, M., Koskimies, J., Vitt, U., Cranfield, M., Vuojolainen, K., Kallio, J. P., Olkkonen, V. M., Hayashi, M. et al. (2003). Growth differentiation factor-9 induces Smad2 activation and inhibin B production in cultured human granulosa-luteal cells. J. Clin. Endocrinol. Metab.88, 755-762.","DOI":"10.1210\/jc.2002-021317"},{"key":"2021042519094560100_REF21","doi-asserted-by":"crossref","unstructured":"Kruip, T. A. and Dieleman, S. J. (1982). Macroscopic classification of bovine follicles and its validation by micromorphological and steroid biochemical procedures. Reprod. Nutr. Dev.22, 465-473.","DOI":"10.1051\/rnd:19820403"},{"key":"2021042519094560100_REF22","doi-asserted-by":"crossref","unstructured":"Lee, W. S., Otsuka, F., Moore, R. K. and Shimasaki, S. (2001). Effect of bone morphogenetic protein-7 on folliculogenesis and ovulation in the rat. Biol. Reprod.65, 994-999.","DOI":"10.1095\/biolreprod65.4.994"},{"key":"2021042519094560100_REF23","doi-asserted-by":"crossref","unstructured":"Leibfried, L. and First, N. L. (1979). Characterization of bovine follicular oocytes and their ability to mature in vitro. J. Anim. Sci.48, 76-86.","DOI":"10.2527\/jas1979.48176x"},{"key":"2021042519094560100_REF24","doi-asserted-by":"crossref","unstructured":"Li, R., Norman, R. J., Armstrong, D. T. and Gilchrist, R. B. (2000). Oocyte-secreted factor(s) determine functional differences between bovine mural granulosa cells and cumulus cells. Biol. Reprod.63, 839-845.","DOI":"10.1095\/biolreprod63.3.839"},{"key":"2021042519094560100_REF25","doi-asserted-by":"crossref","unstructured":"Lin, S. Y., Morrison, J. R., Phillips, D. J. and de Kretser, D. M. (2003). Regulation of ovarian function by the TGF-beta superfamily and follistatin. Reproduction126, 133-148.","DOI":"10.1530\/rep.0.1260133"},{"key":"2021042519094560100_REF26","doi-asserted-by":"crossref","unstructured":"Luciano, A. M., Modina, S., Gandolfi, F., Lauria, A. and Armstrong, D. T. (2000). Effect of cell-to-cell contact on in vitro deoxyribonucleic acid synthesis and apoptosis responses of bovine granulosa cells to insulin-like growth factor-I and epidermal growth factor. Biol. Reprod.63, 1580-1585.","DOI":"10.1095\/biolreprod63.6.1580"},{"key":"2021042519094560100_REF27","doi-asserted-by":"crossref","unstructured":"Luo, G., Hofmann, C., Bronckers, A. L., Sohocki, M., Bradley, A. and Karsenty, G. (1995). BMP-7 is an inducer of nephrogenesis, and is also required for eye development and skeletal patterning. Genes Dev.9, 2808-2820.","DOI":"10.1101\/gad.9.22.2808"},{"key":"2021042519094560100_REF28","unstructured":"Mariana, P. D., Monniaux, D., Driancourt, M. A. and Mauleon, P. (1991). Folliculogenesis. Reproduction in Domestic Animals. San Diego: Academic Press."},{"key":"2021042519094560100_REF29","doi-asserted-by":"crossref","unstructured":"Mazerbourg, S., Klein, C., Roh, J., Kaivo-Oja, N., Mottershead, D. G., Korchynskyi, O., Ritvos, O. and Hsueh, A. J. (2004). Growth differentiation factor-9 signaling is mediated by the type I receptor, activin receptor-like kinase 5. Mol. Endocrinol.18, 653-665.","DOI":"10.1210\/me.2003-0393"},{"key":"2021042519094560100_REF30","doi-asserted-by":"crossref","unstructured":"McNatty, K. P., Moore, L. G., Hudson, N. L., Quirke, L. D., Lawrence, S. B., Reader, K., Hanrahan, J. P., Smith, P., Groome, N. P., Laitinen, M. et al. (2004). The oocyte and its role in regulating ovulation rate: a new paradigm in reproductive biology. Reproduction128, 379-386.","DOI":"10.1530\/rep.1.00280"},{"key":"2021042519094560100_REF31","unstructured":"McNatty, K. P., Juengel, J. L., Reader, K. L., Lun, S., Myllymaa, S., Lawrence, S. B., Western, A., Meerasahib, M. F., Mottershead, D. G., Groome, N. P. et al. (2005). Bone morphogenetic protein 15 and growth differentiation factor 9 co-operate to regulate granulosa cell function. Reproduction129, 473-480."},{"key":"2021042519094560100_REF32","doi-asserted-by":"crossref","unstructured":"Merino, R., Rodriguez-Leon, J., Macias, D., Ganan, Y., Economides, A. N. and Hurle, J. M. (1999). The BMP antagonist Gremlin regulates outgrowth, chondrogenesis and programmed cell death in the developing limb. Development126, 5515-5522.","DOI":"10.1242\/dev.126.23.5515"},{"key":"2021042519094560100_REF33","doi-asserted-by":"crossref","unstructured":"Oltvai, Z. N., Milliman, C. L. and Korsmeyer, S. J. (1993). Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell74, 609-619.","DOI":"10.1016\/0092-8674(93)90509-O"},{"key":"2021042519094560100_REF34","doi-asserted-by":"crossref","unstructured":"Otsuka, F., Moore, R. K., Iemura, S., Ueno, N. and Shimasaki, S. (2001). Follistatin inhibits the function of the oocyte-derived factor BMP-15. Biochem. Biophys. Res. Commun.289, 961-966.","DOI":"10.1006\/bbrc.2001.6103"},{"key":"2021042519094560100_REF35","doi-asserted-by":"crossref","unstructured":"Pangas, S. A., Jorgez, C. J. and Matzuk, M. M. (2004). Growth differentiation factor 9 regulates expression of the bone morphogenetic protein antagonist gremlin. J. Biol. Chem.279, 32281-32286.","DOI":"10.1074\/jbc.M403212200"},{"key":"2021042519094560100_REF36","doi-asserted-by":"crossref","unstructured":"Roh, J. S., Bondestam, J., Mazerbourg, S., Kaivo-Oja, N., Groome, N., Ritvos, O. and Hsueh, A. J. (2003). Growth differentiation factor-9 stimulates inhibin production and activates Smad2 in cultured rat granulosa cells. Endocrinology144, 172-178.","DOI":"10.1210\/en.2002-220618"},{"key":"2021042519094560100_REF37","doi-asserted-by":"crossref","unstructured":"Shimasaki, S., Moore, R. K., Otsuka, F. and Erickson, G. F. (2004). The bone morphogenetic protein system in mammalian reproduction. Endocr. Rev.25, 72-101.","DOI":"10.1210\/er.2003-0007"},{"key":"2021042519094560100_REF38","doi-asserted-by":"crossref","unstructured":"Sudo, S., Avsian-Kretchmer, O., Wang, L. S. and Hsueh, A. J. (2004). Protein related to DAN and cerberus is a bone morphogenetic protein antagonist that participates in ovarian paracrine regulation. J. Biol. Chem.279, 23134-23141.","DOI":"10.1074\/jbc.M402376200"},{"key":"2021042519094560100_REF39","doi-asserted-by":"crossref","unstructured":"Tajima, K., Orisaka, M., Hosokawa, K., Amsterdam, A. and Kotsuji, F. (2002). Effects of ovarian theca cells on apoptosis and proliferation of granulosa cells: changes during bovine follicular maturation. Biol. Reprod.66, 1635-1639.","DOI":"10.1095\/biolreprod66.6.1635"},{"key":"2021042519094560100_REF40","doi-asserted-by":"crossref","unstructured":"Van Wezel, I. L., Dharmarajan, A. M., Lavranos, T. C. and Rodgers, R. J. (1999). Evidence for alternative pathways of granulosa cell death in healthy and slightly atretic bovine antral follicles. Endocrinology140, 2602-2612.","DOI":"10.1210\/endo.140.6.6758"},{"key":"2021042519094560100_REF41","doi-asserted-by":"crossref","unstructured":"Vitt, U. A., Mazerbourg, S., Klein, C. and Hsueh, A. J. (2002). Bone morphogenetic protein receptor type II is a receptor for growth differentiation factor-9. Biol. Reprod.67, 473-480.","DOI":"10.1095\/biolreprod67.2.473"},{"key":"2021042519094560100_REF42","doi-asserted-by":"crossref","unstructured":"Weil, M., Jacobson, M. D., Coles, H. S., Davies, T. J., Gardner, R. L., Raff, K. D. and Raff, M. C. (1996). Constitutive expression of the machinery for programmed cell death. J. Cell Biol.133, 1053-1059.","DOI":"10.1083\/jcb.133.5.1053"},{"key":"2021042519094560100_REF43","doi-asserted-by":"crossref","unstructured":"Yang, M. Y. and Rajamahendran, R. (2000). Morphological and biochemical identification of apoptosis in small, medium, and large bovine follicles and the effects of follicle-stimulating hormone and insulin-like growth factor-I on spontaneous apoptosis in cultured bovine granulosa cells. Biol. Reprod.62, 1209-1217.","DOI":"10.1095\/biolreprod62.5.1209"},{"key":"2021042519094560100_REF44","doi-asserted-by":"crossref","unstructured":"Yuan, Y. Q., Peelman, L. J., Williams, J. L., Van Zeveren, A., de Kruif, A., Law, A. and Van Soom, A. (2004). Mapping and transcription profiling of CASP1, 3, 6, 7 and 8 in relation to caspase activity in the bovine cumulus-oocyte complex. Anim. Genet.35, 234-237.","DOI":"10.1111\/j.1365-2052.2004.01120.x"}],"container-title":["Journal of Cell Science"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/jcs\/article-pdf\/118\/22\/5257\/1523820\/5257.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/jcs\/article-pdf\/118\/22\/5257\/1523820\/5257.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,5]],"date-time":"2023-05-05T03:36:06Z","timestamp":1683257766000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/jcs\/article\/118\/22\/5257\/28599\/Oocytes-prevent-cumulus-cell-apoptosis-by"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2005,11,15]]},"references-count":44,"journal-issue":{"issue":"22","published-print":{"date-parts":[[2005,11,15]]}},"URL":"https:\/\/doi.org\/10.1242\/jcs.02644","relation":{},"ISSN":["1477-9137","0021-9533"],"issn-type":[{"value":"1477-9137","type":"electronic"},{"value":"0021-9533","type":"print"}],"subject":[],"published":{"date-parts":[[2005,11,15]]}}}