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2 August 2021 Deletion of Gremlin-2 alters estrous cyclicity and disrupts female fertility in mice
Robert T. Rydze, Bethany K. Patton, Shawn M. Briley, Hannia Salazar Torralba, Gregory Gipson, Rebecca James, Aleksandar Rajkovic, Thomas Thompson, Stephanie A. Pangas
Author Affiliations +
Abstract

Members of the differential screening-selected gene aberrative in neuroblastoma (DAN) protein family are developmentally conserved extracellular binding proteins that antagonize bone morphogenetic protein (BMP) signaling. This protein family includes the Gremlin proteins, GREM1 and GREM2, which have key functions during embryogenesis and adult physiology. While BMPs play essential roles in ovarian follicle development, the role of the DAN family in female reproductive physiology is less understood. We generated mice null for Grem2 to determine its role in female reproduction in addition to screening patients with primary ovarian insufficiency (POI) for variants in GREM2. Grem2–/– mice are viable, but female Grem2–/– mice have diminished fecundity and irregular estrous cycles. This is accompanied by significantly reduced production of ovarian anti-Müllerian hormone (AMH) from small growing follicles, leading to a significant decrease in serum AMH. Surprisingly, as AMH is a well-established marker of the ovarian reserve, morphometric analysis of ovarian follicles showed maintenance of primordial follicles in Grem2–/– mice like wild-type (WT) littermates. While Grem2 mRNA transcripts were not detected in the pituitary, Grem2 is expressed in hypothalami of WT female mice, suggesting the potential for dysfunction in multiple tissues composing the hypothalamic–pituitary-ovarian axis that contribute to the subfertility phenotype. Additionally, screening 106 women with POI identified one individual with a heterozygous variant in GREM2 that lies within the predicted BMP-GREM2 interface. In total, these data suggest that Grem2 is necessary for female fecundity by playing a novel role in regulating the HPO axis and contributing to female reproductive disease.

Summary sentence

Female mice homozygous null for the BMP antagonist, Grem2, shows a complex reproductive phenotype, but which appears to primarily result from disruptions in the hypothalamic–pituitaryovarian axis leading to irregular estrous cycles.

Graphical Abstract

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© The Author(s) 2021. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
Robert T. Rydze, Bethany K. Patton, Shawn M. Briley, Hannia Salazar Torralba, Gregory Gipson, Rebecca James, Aleksandar Rajkovic, Thomas Thompson, and Stephanie A. Pangas "Deletion of Gremlin-2 alters estrous cyclicity and disrupts female fertility in mice," Biology of Reproduction 105(5), 1205-1220, (2 August 2021). https://doi.org/10.1093/biolre/ioab148
Received: 16 March 2021; Accepted: 27 July 2021; Published: 2 August 2021
KEYWORDS
folliculogenesis
Gremlin
infertility
ovary
reproduction
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