Signalling Pathways Mediating Specific Synergistic Interactions Between GDF9 and BMP15

Overview

Journal Mol Hum Reprod

Specialties Molecular Biology
Reproductive Medicine

Date 2011 Sep 14

PMID 21911477

Citations 32

Authors

David G Mottershead

Lesley J Ritter

Robert B Gilchrist

Affiliations

Soon will be listed here.

Abstract

Growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are two proteins selectively expressed in the oocyte which are essential for normal fertility. Both of these proteins are members of the transforming growth factor beta (TGF-β) superfamily and as such are produced as pre-proproteins, existing after proteolytic processing as a complex of the respective pro and mature regions. Previous work has shown that these two proteins interact both at the genetic and cellular signalling levels. In this study, our aim was to determine if the purified mature regions of GDF9 and BMP15 exhibit synergistic interactions on granulosa cells and to determine if such interactions are specific to these two proteins. We have used primary cultures of murine granulosa cells and [(3)H]-thymidine incorporation or transcriptional reporter assays as our readouts. We observed clear synergistic interactions between the mature regions of GDF9 and BMP15 when either DNA synthesis or SMAD3 signalling were examined. GDF9/BMP15 synergistic interactions were specific such that neither factor could be replaced by an analogous TGF-β superfamily member. The GDF9/BMP15 synergistic signalling response was inhibited by the SMAD2/3 phosphorylation inhibitor SB431542, as well as inhibition of the mitogen-activated protein kinase or rous sarcoma oncogene (SRC) signalling pathways, but not the nuclear factor kappa B pathway. In this study, we show that purified mature regions of GDF9 and BMP15 synergistically interact in a specific manner which is not dependent on the presence of a pro-region. This synergistic interaction is targeted at the SMAD3 pathway, and is dependent on ERK1/2 and SRC kinase signalling.

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References

Su Y, Wu X, OBrien M, Pendola F, Denegre J, Matzuk M . Synergistic roles of BMP15 and GDF9 in the development and function of the oocyte-cumulus cell complex in mice: genetic evidence for an oocyte-granulosa cell regulatory loop. Dev Biol. 2004; 276(1):64-73. DOI: 10.1016/j.ydbio.2004.08.020. View

McPherron A, Lee S . GDF-3 and GDF-9: two new members of the transforming growth factor-beta superfamily containing a novel pattern of cysteines. J Biol Chem. 1993; 268(5):3444-9. View

McNatty K, Juengel J, Reader K, Lun S, Myllymaa S, Lawrence S . Bone morphogenetic protein 15 and growth differentiation factor 9 co-operate to regulate granulosa cell function. Reproduction. 2005; 129(4):473-80. DOI: 10.1530/rep.1.0511. View

Gilchrist R, Ritter L, Cranfield M, Jeffery L, Amato F, Scott S . Immunoneutralization of growth differentiation factor 9 reveals it partially accounts for mouse oocyte mitogenic activity. Biol Reprod. 2004; 71(3):732-9. DOI: 10.1095/biolreprod.104.028852. View

Dixit H, Rao L, Padmalatha V, Kanakavalli M, Deenadayal M, Gupta N . Missense mutations in the BMP15 gene are associated with ovarian failure. Hum Genet. 2006; 119(4):408-15. DOI: 10.1007/s00439-006-0150-0. View

Reader K, Heath D, Lun S, McIntosh C, Western A, Littlejohn R . Signalling pathways involved in the cooperative effects of ovine and murine GDF9+BMP15-stimulated thymidine uptake by rat granulosa cells. Reproduction. 2011; 142(1):123-31. DOI: 10.1530/REP-10-0490. View

Pulkki M, Myllymaa S, Pasternack A, Lun S, Ludlow H, Al-Qahtani A . The bioactivity of human bone morphogenetic protein-15 is sensitive to C-terminal modification: characterization of the purified untagged processed mature region. Mol Cell Endocrinol. 2010; 332(1-2):106-15. DOI: 10.1016/j.mce.2010.10.002. View

McNatty K, Lawrence S, Groome N, Meerasahib M, Hudson N, Whiting L . Meat and Livestock Association Plenary Lecture 2005. Oocyte signalling molecules and their effects on reproduction in ruminants. Reprod Fertil Dev. 2006; 18(4):403-12. DOI: 10.1071/rd05104. View

Korchynskyi O, Ten Dijke P . Identification and functional characterization of distinct critically important bone morphogenetic protein-specific response elements in the Id1 promoter. J Biol Chem. 2001; 277(7):4883-91. DOI: 10.1074/jbc.M111023200. View

10.

Laitinen M, Vuojolainen K, Jaatinen R, KETOLA I, Aaltonen J, Lehtonen E . A novel growth differentiation factor-9 (GDF-9) related factor is co-expressed with GDF-9 in mouse oocytes during folliculogenesis. Mech Dev. 1998; 78(1-2):135-40. DOI: 10.1016/s0925-4773(98)00161-0. View

11.

Dong J, Albertini D, Nishimori K, Kumar T, Lu N, Matzuk M . Growth differentiation factor-9 is required during early ovarian folliculogenesis. Nature. 1996; 383(6600):531-5. DOI: 10.1038/383531a0. View

12.

Juengel J, McNatty K . The role of proteins of the transforming growth factor-beta superfamily in the intraovarian regulation of follicular development. Hum Reprod Update. 2005; 11(2):143-60. DOI: 10.1093/humupd/dmh061. View

13.

Wei L, Liang X, Fang C, Zhang M . Abnormal expression of growth differentiation factor 9 and bone morphogenetic protein 15 in stimulated oocytes during maturation from women with polycystic ovary syndrome. Fertil Steril. 2011; 96(2):464-8. DOI: 10.1016/j.fertnstert.2011.05.036. View

14.

Vitt U, Mazerbourg S, Klein C, Hsueh A . Bone morphogenetic protein receptor type II is a receptor for growth differentiation factor-9. Biol Reprod. 2002; 67(2):473-80. DOI: 10.1095/biolreprod67.2.473. View

15.

Hickey T, Marrocco D, Amato F, Ritter L, Norman R, Gilchrist R . Androgens augment the mitogenic effects of oocyte-secreted factors and growth differentiation factor 9 on porcine granulosa cells. Biol Reprod. 2005; 73(4):825-32. DOI: 10.1095/biolreprod.104.039362. View

16.

Hoekstra C, Zhao Z, Lambalk C, Willemsen G, Martin N, Boomsma D . Dizygotic twinning. Hum Reprod Update. 2007; 14(1):37-47. DOI: 10.1093/humupd/dmm036. View

17.

McIntosh C, Lun S, Lawrence S, Western A, McNatty K, Juengel J . The proregion of mouse BMP15 regulates the cooperative interactions of BMP15 and GDF9. Biol Reprod. 2008; 79(5):889-96. DOI: 10.1095/biolreprod.108.068163. View

18.

Kaivo-Oja N, Mottershead D, Mazerbourg S, Myllymaa S, Duprat S, Gilchrist R . Adenoviral gene transfer allows Smad-responsive gene promoter analyses and delineation of type I receptor usage of transforming growth factor-beta family ligands in cultured human granulosa luteal cells. J Clin Endocrinol Metab. 2004; 90(1):271-8. DOI: 10.1210/jc.2004-1288. View

19.

Moore R, Otsuka F, Shimasaki S . Molecular basis of bone morphogenetic protein-15 signaling in granulosa cells. J Biol Chem. 2002; 278(1):304-10. DOI: 10.1074/jbc.M207362200. View

20.

Edwards S, Reader K, Lun S, Western A, Lawrence S, McNatty K . The cooperative effect of growth and differentiation factor-9 and bone morphogenetic protein (BMP)-15 on granulosa cell function is modulated primarily through BMP receptor II. Endocrinology. 2007; 149(3):1026-30. DOI: 10.1210/en.2007-1328. View