Mottershead, DG, Sugimura, S, Al-Musawi, SL, Li, J-J, Richani, D, White, MA, Martin, GA, Trotta, AP, Ritter, LJ, Shi, J, Mueller, TD, Harrison, CA and Gilchrist, RB (2015) Cumulin, an Oocyte-secreted Heterodimer of the Transforming Growth Factor-β Family, Is a Potent Activator of Granulosa Cells and Improves Oocyte Quality. Journal of Biological Chemistry, 290 (39). 24007 -24020. ISSN 1083-351X

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Growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are oocyte-specific growth factors with central roles in mammalian reproduction, regulating species-specific fecundity, ovarian follicular somatic cell differentiation, and oocyte quality. In the human, GDF9 is produced in a latent form, the mechanism of activation being an open question. Here, we produced a range of recombinant GDF9 and BMP15 variants, examined their in silico and physical interactions and their effects on ovarian granulosa cells (GC) and oocytes. We found that the potent synergistic actions of GDF9 and BMP15 on GC can be attributed to the formation of a heterodimer, which we have termed cumulin. Structural modeling of cumulin revealed a dimerization interface identical to homodimeric GDF9 and BMP15, indicating likely formation of a stable complex. This was confirmed by generation of recombinant heterodimeric complexes of pro/mature domains (pro-cumulin) and covalent mature domains (cumulin). Both pro-cumulin and cumulin exhibited highly potent bioactivity on GC, activating both SMAD2/3 and SMAD1/5/8 signaling pathways and promoting proliferation and expression of a set of genes associated with oocyte-regulated GC differentiation. Cumulin was more potent than pro-cumulin, pro-GDF9, pro-BMP15, or the two combined on GC. However, on cumulus-oocyte complexes, pro-cumulin was more effective than all other growth factors at notably improving oocyte quality as assessed by subsequent day 7 embryo development. Our results support a model of activation for human GDF9 dependent on cumulin formation through heterodimerization with BMP15. Oocyte-secreted cumulin is likely to be a central regulator of fertility in mono-ovular mammals.

Item Type: Article
Additional Information: © The Authors. This is the final published version of the article (version of record). It first appeared online via American Society for Biochemistry and Molecular Biology at - please refer to any applicable terms of use of the publisher.
Uncontrolled Keywords: IVM, SMAD transcription factor, bone morphogenetic protein (BMP), cumulin, cumulus granulosa, cell, growth differentiation factor, oocyte quality, protein assembly, protein secretion, transforming growth factor beta (TGF-β), Animals, Bone Morphogenetic Protein 15, Female, Granulosa Cells, Growth Differentiation Factor 9, Humans, Mice, Oocytes, Protein Multimerization, Signal Transduction, Smad Proteins
Subjects: Q Science > QR Microbiology
R Medicine > R Medicine (General)
Divisions: Faculty of Medicine and Health Sciences > Institute for Science and Technology in Medicine
Related URLs:
Depositing User: Symplectic
Date Deposited: 14 Feb 2019 09:34
Last Modified: 14 Feb 2019 09:41

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