Skip to main content

Advertisement

SpringerLink
Log in

Abundance of Dual Specificity Phosphatase (DUSP) 1 and DUSP6 mRNA Is Regulated by Hippo Signaling in Bovine Pre-ovulatory Granulosa Cells

  • Reproductive Biology: Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Ovulatory disorders are a major cause of infertility in humans as well as economically important species. In physiological conditions, the LH surge induces the expression of epidermal growth factor (EGF)-like ligands that activate the EGR receptor (EGFR) and subsequently the mitogen-activated protein kinase (MAPK) pathway. The magnitude and duration of MAPK phosphorylation are regulated by dual-specificity phosphatases (DUSPs). Besides this well-known cascade, other signaling pathways such as the Hippo pathway modulate the ovulatory cascade and are reported to crosstalk with MAPK signaling. Here, we tested the hypothesis that LH and the Hippo pathway regulate DUSP expression in bovine pre-ovulatory granulosa cells. The abundance of DUSP6 mRNA but not DUSP1 was decreased by LH (P < 0.05). Cells were then pre-treated (1 h) with two inhibitors of Hippo signaling, verteporfin (1 µM) or peptide-17 (25 µM), before exposure for 6 h to LH or to EGF. Treatment with verteporfin increased DUSP1 mRNA levels (P < 0.05) in the presence or absence of EGF or LH and treatment with peptide-17 increased DUSP6 and not DUSP1 mRNA abundance. These data indicate a differential regulation of DUSP1 and DUSP6 mRNA by the Hippo pathway in pre-ovulatory granulosa cells, which suggests a complex control of MAPK signaling around ovulation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data Availability

The data are available on request.

Code Availability

Not applicable.

References

  1. Carson SA, Kallen AN. Diagnosis and management of infertility: a review. JAMA. 2021;326:65–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Walsh SW, Williams EJ, Evans ACO. A review of the causes of poor fertility in high milk producing dairy cows. Anim Reprod Sci. 2011;123:127–38.

    Article  CAS  PubMed  Google Scholar 

  3. Park J-Y, Su Y-Q, Ariga M, Law E, Jin S-LC, Conti M. EGF-like growth factors as mediators of LH action in the ovulatory follicle. Science. 2004;303:682–4.

    Article  CAS  PubMed  Google Scholar 

  4. Panigone S, Hsieh M, Fu M, Persani L, Conti M. Luteinizing hormone signaling in preovulatory follicles involves early activation of the epidermal growth factor receptor pathway. Mol Endocrinol. 2008;22:924–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Shimada M, Hernandez-Gonzalez I, Gonzalez-Robayna I, Richards JS. Paracrine and autocrine regulation of epidermal growth factor-like factors in cumulus oocyte complexes and granulosa cells: key roles for prostaglandin synthase 2 and progesterone receptor. Mol Endocrinol. 2006;20:1352–65.

    Article  CAS  PubMed  Google Scholar 

  6. Fan HY, Liu Z, Shimada M, Sterneck E, Johnson PF, Hedrick SM, Richards JS. MAPK3/1 (ERK1/2) in ovarian granulosa cells are essential for female fertility. Science. 2009;324:938–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Madogwe E, Schuermann Y, Siddappa D, Bordignon V, Roux PP, Duggavathi R. Sustained ERK1/2 signaling is necessary for follicular rupture during ovulation in mice. Reproduction. 2021;161:183–93.

    Article  CAS  PubMed  Google Scholar 

  8. Hong W, Guan K-L. The YAP and TAZ transcription co-activators: key downstream effectors of the mammalian Hippo pathway. Semin Cell Dev Biol. 2012;23:785–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kawamura K, Cheng Y, Suzuki N, Deguchi M, Sato Y, Takae S, Ho C-H, Kawamura N, Tamura M, Hashimoto S, Sugishita Y, Morimoto Y, Hosoi Y, Yoshioka N, Ishizuka B, Hsueh AJ. Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment. Proc Natl Sci U S A. 2013;110:17474.

    Article  CAS  Google Scholar 

  10. Lv X, He C, Huang C, Wang H, Hua G, Wang Z, Zhou J, Chen X, Ma B, Timm BK, Maclin V, Dong J, Rueda BR, Davis JS, Wang C. Timely expression and activation of YAP1 in granulosa cells is essential for ovarian follicle development. FASEB J. 2019;33:10049–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sun T, Diaz FJ. Ovulatory signals alter granulosa cell behavior through YAP1 signaling. Reprod Biol Endocrinol. 2019;17:113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Godin P, Tsoi MF, Morin M, Gévry N, Boerboom D. The granulosa cell response to luteinizing hormone is partly mediated by YAP1-dependent induction of amphiregulin. Cell Commun Signal. 2022;20:72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Dos Santos EC, Lalonde-Larue A, Antoniazzi AQ, Barreta MH, Price CA, Dias Gonçalves PB, Portela VM, Zamberlam G. YAP signaling in preovulatory granulosa cells is critical for the functioning of the EGF network during ovulation. Mol Cell Endocrinol. 2022;541:111524.

    Article  PubMed  Google Scholar 

  14. Patterson Kate I, Brummer T, Brien Philippa M, Daly Roger J. Dual-specificity phosphatases: critical regulators with diverse cellular targets. Biochem J. 2009;418:475.

    Article  CAS  PubMed  Google Scholar 

  15. Kidger AM, Keyse SM. The regulation of oncogenic Ras/ERK signalling by dual-specificity mitogen activated protein kinase phosphatases (MKPs). Semin Cell Dev Biol. 2016;50:125–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Maillet M, Purcell NH, Sargent MA, York AJ, Bueno OF, Molkentin JD. DUSP6 (MKP3) null mice show enhanced ERK1/2 phosphorylation at baseline and increased myocyte proliferation in the heart affecting disease susceptibility. J Biol Chem. 2008;283:31246–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Dorfman K, Carrasco D, Gruda M, Ryan C, Lira SA, Bravo R. Disruption of the erp/mkp-1 gene does not affect mouse development: normal MAP kinase activity in ERP/MKP-1-deficient fibroblasts. Oncogene. 1996;13:925–31.

    CAS  PubMed  Google Scholar 

  18. Khan DR, Guillemette C, Sirard MA, Richard FJ. Characterization of FSH signalling networks in bovine cumulus cells: a perspective on oocyte competence acquisition. Mol Hum Reprod. 2015;21:688–701.

    Article  CAS  PubMed  Google Scholar 

  19. Khan DR, Guillemette C, Sirard MA, Richard FJ. Transcriptomic analysis of cyclic AMP response in bovine cumulus cells. Physiol Genomics. 2015;47:432–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Herndon MK, Law NC, Donaubauer EM, Kyriss B, Hunzicker-Dunn M. Forkhead box O member FOXO1 regulates the majority of follicle-stimulating hormone responsive genes in ovarian granulosa cells. Mol Cell Endocrinol. 2016;434:116–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Reizel Y, Elbaz J, Dekel N. Sustained activity of the EGF receptor is an absolute requisite for LH-induced oocyte maturation and cumulus expansion. Mol Endocrinol. 2010;24:402–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Relav L, Estienne A, Price CA. Dual-specificity phosphatase 6 (DUSP6) mRNA and protein abundance is regulated by fibroblast growth factor 2 in sheep granulosa cells and inhibits c-Jun N-terminal kinase (MAPK8) phosphorylation. Mol Cell Endocrinol. 2021;531:111297.

    Article  CAS  PubMed  Google Scholar 

  23. Relav L, Price CA. Regulation of dual specificity phosphatases by fibroblast growth factor signaling pathways in bovine granulosa cells. Reproduction. 2021;162:367–74.

    Article  CAS  PubMed  Google Scholar 

  24. Queipo MJ, Gil-Redondo JC, Morente V, Ortega F, Miras-Portugal MT, Delicado EG, Pérez-Sen R. P2X7 nucleotide and EGF receptors exert dual modulation of the dual-specificity phosphatase 6 (MKP-3) in granule neurons and astrocytes, contributing to negative feedback on ERK signaling. Front Mol Neurosci. 2018;10:448.

  25. Fu X-H, Chen C-Z, Li S, Han D-X, Wang Y-J, Yuan B, Gao Y, Zhang J-B, Jiang H. Dual-specificity phosphatase 1 regulates cell cycle progression and apoptosis in cumulus cells by affecting mitochondrial function, oxidative stress, and autophagy. Am J Physiol-Cell Ph. 2019;317:C1183–93.

    Article  CAS  Google Scholar 

  26. Portela VM, Zamberlam G, Goncalves PB, de Oliveira JF, Price CA. Role of Angiotensin II in the periovulatory epidermal growth factor-like cascade in bovine granulosa cells in vitro. Biol Reprod. 2011;85:1167–74.

    Article  CAS  PubMed  Google Scholar 

  27. Zamberlam G, Sahmi F, Price CA. Nitric oxide synthase activity is critical for the preovulatory epidermal growth factor-like cascade induced by luteinizing hormone in bovine granulosa cells. Free Radic Biol Med. 2014;74:237–44.

    Article  CAS  PubMed  Google Scholar 

  28. Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001;29:e45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhang Z, Lin Z, Zhou Z, Shen HC, Yan SF, Mayweg AV, Xu Z, Qin N, Wong JC, Zhang Z, Rong Y, Fry DC, Hu T. Structure-based design and synthesis of potent cyclic peptides inhibiting the YAP–TEAD protein–protein interaction. ACS Med Chem Lett. 2014;5:993–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Liu-Chittenden Y, Huang B, Shim JS, Chen Q, Lee S-J, Anders RA, Liu JO, Pan D. Genetic and pharmacological disruption of the TEAD–YAP complex suppresses the oncogenic activity of YAP. Genes Dev. 2012;26:1300–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yuan Y, Salinas Parra N, Chen Q, Iglesias-Bartolome R. Oncogenic hedgehog-smoothened signaling depends on YAP1-TAZ/TEAD transcription to restrain differentiation in basal cell carcinoma. J Invest Dermatol. 2022;142:65-76.e67.

    Article  CAS  PubMed  Google Scholar 

  32. Manderfield LJ, Aghajanian H, Engleka KA, Lim LY, Liu F, Jain R, Li L, Olson EN, Epstein JA. Hippo signaling is required for Notch-dependent smooth muscle differentiation of neural crest. Development. 2015;142:2962–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Strano S, Munarriz E, Rossi M, Castagnoli L, Shaul Y, Sacchi A, Oren M, Sudol M, Cesareni G, Blandino G. Physical interaction with Yes-associated protein enhances p73 transcriptional activity. J Biol Chem. 2001;276:15164–73.

    Article  CAS  PubMed  Google Scholar 

  34. Varelas X, Samavarchi-Tehrani P, Narimatsu M, Weiss A, Cockburn K, Larsen BG, Rossant J, Wrana JL. The crumbs complex couples cell density sensing to hippo-dependent control of the TGF-β-SMAD pathway. Dev Cell. 2010;19:831–44.

    Article  CAS  PubMed  Google Scholar 

  35. Jono H, Xu H, Kai H, Lim DJ, Kim YS, Feng X-H, Li J-D. Transforming growth factor -β-Smad signaling pathway negatively regulates nontypeable haemophilus influenzae-induced muc5ac mucin transcription via mitogen-activated protein kinase (MAPK) phosphatase-1-dependent inhibition of p38 MAPK. J Biol Chem. 2003;278:27811–9.

    Article  CAS  PubMed  Google Scholar 

  36. Jeong SB, Das R, Kim D-H, Lee S, Oh HI, Jo S, Lee Y, Kim J, Park S, Choi DK, Moon UY, Kwon O-B, Namkung W, Lee S, Cho BC, Woo J, Seo Y. Anticancer effect of verteporfin on non-small cell lung cancer via downregulation of ANO1. Biomed Pharmacother. 2022;153:113373.

    Article  CAS  PubMed  Google Scholar 

  37. Kuramoto K, Yamamoto M, Suzuki S, Sanomachi T, Togashi K, Seino S, Kitanaka C, Okada M. Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells. FEBS J. 2020;287:2023–36.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by funding from Fonds de Recherche du Québec—Nature et Technologies for CAP and by funding from the Natural Sciences and Engineering Research Council of Canada (NSERC) for GZ. RL received a scholarship from Collectivité Territoriale de Martinique.

Author information

Author notes

  1. Lauriane Relav

    Present address: Institut de Pharmacologie Moléculaire Et Cellulaire, CNRS UMR7275, Sophia Antipolis, 660 Route Des Lucioles, 06560, Valbonne, France

  2. Lauriane Relav and Esdras Corrêa dos Santos contributed equally to this work.

Authors and Affiliations

  1. Centre de Recherche en Reproduction Animale, Faculté de Médecine Vétérinaire, Université de Montréal, St-Hyacinthe, QC, J2S 7C6, Canada

    Lauriane Relav, Esdras Corrêa Dos Santos, Gustavo Zamberlam & Christopher A. Price

Authors
  1. Lauriane Relav
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Esdras Corrêa Dos Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gustavo Zamberlam
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christopher A. Price
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Gustavo Zamberlam or Christopher A. Price.

Ethics declarations

IRB Approval

This work did not involve animals or humans, therefore no Institutional Review Board or Ethics Committee approval is required.

Ethics Approval

Not applicable.

Consent to Participate

Not applicable.

Consent for Publication

All the authors consented to the publication of this work.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Relav, L., Dos Santos, E.C., Zamberlam, G. et al. Abundance of Dual Specificity Phosphatase (DUSP) 1 and DUSP6 mRNA Is Regulated by Hippo Signaling in Bovine Pre-ovulatory Granulosa Cells. Reprod. Sci. 30, 1782–1788 (2023). https://doi.org/10.1007/s43032-022-01142-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43032-022-01142-3

Keywords

Search

Navigation