Cumulin and FSH cooperate to regulate inhibin B and activin B production by human granulosa-lutein cells in vitro

Dulama Richani, Katherine Constance, Shelly Lien, David Agapiou, William A. Stocker, Mark P. Hedger, William Ledger, Jeremy G. Thompson, David M. Robertson, David G Mottershead, Kelly L. Walton, Craig A. Harrison, Robert Gilchrist

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)853-862
Number of pages10
JournalEndocrinology
Volume160
Issue number4
DOIs
Publication statusPublished - 1 Apr 2019

Cite this

Richani, Dulama ; Constance, Katherine ; Lien, Shelly ; Agapiou, David ; Stocker, William A. ; Hedger, Mark P. ; Ledger, William ; Thompson, Jeremy G. ; Robertson, David M. ; Mottershead, David G ; Walton, Kelly L. ; Harrison, Craig A. ; Gilchrist, Robert. / Cumulin and FSH cooperate to regulate inhibin B and activin B production by human granulosa-lutein cells in vitro. In: Endocrinology. 2019 ; Vol. 160, No. 4. pp. 853-862.
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title = "Cumulin and FSH cooperate to regulate inhibin B and activin B production by human granulosa-lutein cells in vitro",
abstract = "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.",
author = "Dulama Richani and Katherine Constance and Shelly Lien and David Agapiou and Stocker, {William A.} and Hedger, {Mark P.} and William Ledger and Thompson, {Jeremy G.} and Robertson, {David M.} and Mottershead, {David G} and Walton, {Kelly L.} and Harrison, {Craig A.} and Robert Gilchrist",
year = "2019",
month = "4",
day = "1",
doi = "10.1210/en.2018-01026",
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pages = "853--862",
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Richani, D, Constance, K, Lien, S, Agapiou, D, Stocker, WA, Hedger, MP, Ledger, W, Thompson, JG, Robertson, DM, Mottershead, DG, Walton, KL, Harrison, CA & Gilchrist, R 2019, 'Cumulin and FSH cooperate to regulate inhibin B and activin B production by human granulosa-lutein cells in vitro' Endocrinology, vol. 160, no. 4, pp. 853-862. https://doi.org/10.1210/en.2018-01026, https://doi.org/10.1210/en.2018-01026

Cumulin and FSH cooperate to regulate inhibin B and activin B production by human granulosa-lutein cells in vitro. / Richani, Dulama; Constance, Katherine ; Lien, Shelly ; Agapiou, David; Stocker, William A.; Hedger, Mark P.; Ledger, William; Thompson, Jeremy G.; Robertson, David M.; Mottershead, David G; Walton, Kelly L.; Harrison, Craig A.; Gilchrist, Robert.

In: Endocrinology, Vol. 160, No. 4, 01.04.2019, p. 853-862.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Cumulin and FSH cooperate to regulate inhibin B and activin B production by human granulosa-lutein cells in vitro

AU - Richani, Dulama

AU - Constance, Katherine

AU - Lien, Shelly

AU - Agapiou, David

AU - Stocker, William A.

AU - Hedger, Mark P.

AU - Ledger, William

AU - Thompson, Jeremy G.

AU - Robertson, David M.

AU - Mottershead, David G

AU - Walton, Kelly L.

AU - Harrison, Craig A.

AU - Gilchrist, Robert

PY - 2019/4/1

Y1 - 2019/4/1

N2 - 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.

AB - 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.

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U2 - 10.1210/en.2018-01026

DO - 10.1210/en.2018-01026

M3 - Article

VL - 160

SP - 853

EP - 862

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 4

ER -