Cumulin and FSH Cooperate to Regulate Inhibin B and Activin B Production by Human Granulosa-Lutein Cells In Vitro

The oocyte-secreted factors bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9) interact functionally, and it is hypothesized that this interaction may be mediated by formation of a GDF9:BMP15 heterodimer termed cumulin. GDF9 and BMP15 regulate folliculogenesis and ovula...

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Bibliographic Details
Published in:Endocrinology (Philadelphia) 2019-04, Vol.160 (4), p.853-862
Main Authors: Richani, Dulama, Constance, Katherine, Lien, Shelly, Agapiou, David, Stocker, William A, Hedger, Mark P, Ledger, William L, Thompson, Jeremy G, Robertson, David M, Mottershead, David G, Walton, Kelly L, Harrison, Craig A, Gilchrist, Robert B
Format: Article
Language:English
Subjects:
Activin
Activins - metabolism
Bone Morphogenetic Protein 15 - pharmacology
Chorionic Gonadotropin - pharmacology
Cooperation
Corpus luteum
Cysteine
Endocrinology
Female
Follicle Stimulating Hormone - pharmacology
Follicle-stimulating hormone
Folliculogenesis
Gametocytes
Gene expression
Granulosa cells
Growth differentiation factor 9
Growth Differentiation Factor 9 - pharmacology
Humans
In vitro fertilization
Inhibin
Inhibins - metabolism
Luteal Cells - drug effects
Luteal Cells - metabolism
Lutein
Mutants
Oocyte Retrieval
Oocytes - drug effects
Oocytes - metabolism
Ovulation
Paracrine signalling
Physiological aspects
Regulators
Secretion
Signal Transduction - drug effects
Somatic cells
Transforming growth factors
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Summary:The oocyte-secreted factors bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9) interact functionally, and it is hypothesized that this interaction may be mediated by formation of a GDF9:BMP15 heterodimer termed cumulin. GDF9 and BMP15 regulate folliculogenesis and ovulation rate and have been shown to regulate inhibin and activin, local regulators of folliculogenesis. The objective of this study was to determine whether cumulin regulates granulosa cell inhibin and activin production and whether this requires cooperation with FSH. Human granulosa-lutein (hGL) cells collected from patients undergoing in vitro fertilization were cultured with or without FSH with various forms of recombinant cumulin (native and cysteine mutants, with or without the prodomains), and cysteine mutant GDF9 or BMP15. Messenger RNA expression of the subunits of inhibins/activins (INHA, INHBA, INHBB) and secretion of inhibin A, inhibin B, and activin B were measured. Mature forms and proforms of cumulin stimulated comparable INHBB mRNA expression and secretion of inhibin B and activin B, whereas GDF9 or BMP15 exhibited no effect. Cumulin, but not GDF9 or BMP15, interacted synergistically with FSH to increase INHBB mRNA and inhibin B expression. FSH markedly stimulated INHA, which encodes the α subunit of inhibin A/B, and suppressed activin B. Cumulin with or without FSH did not significantly alter inhibin A. Together these data demonstrate that cumulin, but not GDF9 or BMP15, exerts paracrine control of FSH-induced regulation of inhibin B and activin B. The prodomains of cumulin may have a minimal role in its actions on granulosa cells.
ISSN:1945-7170
0013-7227
1945-7170
DOI:10.1210/en.2018-01026