University of Oulu

Ville Veikkolainen, Nsrein Ali, Milena Doroszko, Antti Kiviniemi, Ilkka Miinalainen, Claes Ohlsson, Matti Poutanen, Nafis Rahman, Klaus Elenius, Seppo J Vainio, Florence Naillat, Erbb4 regulates the oocyte microenvironment during folliculogenesis, Human Molecular Genetics, Volume 29, Issue 17, 1 September 2020, Pages 2813–2830, https://doi.org/10.1093/hmg/ddaa161

Erbb4 regulates the oocyte microenvironment during folliculogenesis

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Author: Veikkolainen, Ville1; Ali, Nsrein2; Doroszko, Milena3,4;
Organizations: 1Institute of Biomedicine and MediCity Research Laboratory, University of Turku , FI-20520 Turku, Finland
2Organogenesis Laboratory, Department of Medical Biochemistry and Molecular Biology, Biocenter Oulu, University of Oulu , FI-90014 Oulu, Finland
3Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku , FI-20520 Turku, Finland
4Department of Immunology Genetics and Pathology, Section for Neuro-oncology, Uppsala University , 752 36 Uppsala, Sweden
5Electron Microscopy Unit, Biocenter Oulu, University of Oulu, FI-90220 Oulu, Finland
6Institute of Medicine, Sahlgrenska Academy , University of Gothenburg, SE-41345 Gothenburg, Sweden
7Department of Oncology, Turku University Hospital , FI-20520 Turku, Finland
8InfoTech Oulu , Oulu University and Biobank Borealis of Northern Finland, Oulu University Hospital, University of Oulu, FI-90014 Oulu, FINLAND
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 37.1 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2020112693299
Language: English
Published: Oxford University Press, 2020
Publish Date: 2021-07-27
Description:

Abstract

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders leading to infertility in women affecting reproductive, endocrine and metabolic systems. Recent genomewide association studies on PCOS cohorts revealed a single nucleotide polymorphism (SNP) in the ERBB4 receptor tyrosine kinase 4 gene, but its role in ovary development or during folliculogenesis remains poorly understood. Since no genetic animal models mimicking all PCOS reproductive features are available, we conditionally deleted Erbb4 in murine granulosa cells (GCs) under the control of Amh promoter. While we have demonstrated that Erbb4 deletion displayed aberrant ovarian function by affecting the reproductive function (asynchronous oestrous cycle leading to few ovulations and subfertility) and metabolic function (obesity), their ovaries also present severe structural and functional abnormalities (impaired oocyte development). Hormone analysis revealed an up-regulation of serum luteinizing hormone, hyperandrogenism, increased production of ovarian and circulating anti-Müllerian hormone. Our data implicate that Erbb4 deletion in GCs leads to defective intercellular junctions between the GCs and oocytes, causing changes in the expression of genes regulating the local microenvironment of the follicles. In vitro culture assays reducing the level of Erbb4 via shRNAs confirm that Erbb4 is essential for regulating Amh level. In conclusion, our results indicate a functional role for Erbb4 in the ovary, especially during folliculogenesis and its reduced expression plays an important role in reproductive pathophysiology, such as PCOS development.

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Series: Human molecular genetics
ISSN: 0964-6906
ISSN-E: 1460-2083
ISSN-L: 0964-6906
Volume: 29
Issue: 17
Pages: 2813 - 2830
DOI: 10.1093/hmg/ddaa161
OADOI: https://oadoi.org/10.1093/hmg/ddaa161
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Subjects:
Funding: This work was supported by grants from the Academy of Finland Profiling funding to the University of Oulu Profi3 (311934); for S.J.V., by the Academy of Finland (206038, 121647, 250900, 260056), Centre of Excellence Grant 2012–2017 of the Academy of Finland (251314), and Tekes BioRealHealth (24302443); and for F.N., by the Academy of Finland post-doctoral Fellowship (243014583), the Foundations’ Post Doc Pool (Svenska Kulturfonden) and the Finnish Cultural Foundation (Pekka ja Jukka-Pekka Lylykarin rahasto).
Academy of Finland Grant Number: 121647
250900
260056
Detailed Information: 121647 (Academy of Finland Funding decision)
250900 (Academy of Finland Funding decision)
260056 (Academy of Finland Funding decision)
Copyright information: © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.