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Control of Murine Primordial Follicle Growth Activation by IκB/NFκB Signaling

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Abstract

The transcription factor NFκB has been associated with the timing of menopause in a large human genome-wide association study. Furthermore, preclinical studies demonstrate that loss of Tumor necrosis factor alpha (Tnfα) or its receptor Tnfr2 slows primordial follicle growth activation (PFGA). Although Tnfα:receptor signaling stimulates NFκB and may mechanistically link these findings, very little is known about NFκB signaling in PFGA. Because signaling downstream of Tnfα/Tnfr2 ligand/receptor interaction has not been interrogated as relates to PFGA, we evaluated the expression of key NFκB signaling proteins in primordial and growing follicles, as well as during ovarian aging. We show that key members of the NFκB pathway, including subunits, activating kinases, and inhibitory proteins, are expressed in the murine ovary. Furthermore, the subunits p65 and p50, and the cytosolic inhibitory proteins IκBα and IκBβ, are present in ovarian follicles, including at the primordial stage. Finally, we assessed PFGA in genetically modified mice (AKBI) previously demonstrated to be resistant to inflammatory stress-induced NFκB activation due to overexpression of the NFκB inhibitory protein IκBβ. Consistent with the hypothesis that NFκB plays a key role in PFGA, AKBI mice exhibit slower PGFA than wild-type (WT) controls, and their ovaries contain nearly twice the number of primordial follicles as WT both at early and late reproductive ages. These data provide mechanistic insight on the control of PFGA and suggest that targeting NFκB at the level of IκB proteins may be a tractable route to slowing the rate of PFGA in women faced with early ovarian demise.

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Acknowledgments

Sarah McKenna and Leanna Nguyen provided support for experiments performed during this study. Drs. Benjamin Bitler and Damian Guerra are acknowledged for providing invaluable feedback on the manuscript prior to submission.

Funding

C.W. acknowledges support by NIH R01HL132941. J.J. is supported by CU-Anschutz Department of Obstetrics and Gynecology Research Funds.

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Authors and Affiliations

  1. University of Colorado School of Medicine, Aurora, CO, USA

    Clyde J. Wright, Evelyn Llerena Cari, Jeryl Sandoval, Elise Bales, Peter Ka Sam, Miguel A. Zarate, Alex J. Polotsky & Joshua Johnson

  2. Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA

    Clyde J. Wright, Jeryl Sandoval & Miguel A. Zarate

  3. Department of Obstetrics and Gynecology, Division of Reproductive Sciences, University of Colorado Denver (AMC), Building RC2, Room P15 3103, Mail Stop 8613, Aurora, CO, 80045, USA

    Evelyn Llerena Cari, Elise Bales, Peter Ka Sam, Alex J. Polotsky & Joshua Johnson

  4. Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of Colorado Denver (AMC), Aurora, CO, USA

    Alex J. Polotsky & Joshua Johnson

  5. Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA

    Amanda N. Kallen

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Contributions

C.J.W., A.J.P., A.K., J.J. conception and design of research; C.J.W., E.L.C., J.S., E.B., P.K.S., M.A.Z., J.J. performed experiments; C.J.W., E.L.C., J.S., E.B., P.K.S., M.A.Z., A.K., J.J. analyzed data; C.J.W., E.L.C., J.S., E.B., P.K.S., M.A.Z., J.J. interpreted results of experiments; J.J. drafted the manuscript; C.J.W., E.L.C., J.S., J.J. prepared figures; C.J.W., J.J. edited and revised manuscript; C.J.W., E.L.C., J.S., E.B., P.K.S., M.A.Z., A.J.P., A.K., J.J. approved final version of manuscript.

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Correspondence to Clyde J. Wright or Joshua Johnson.

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Wright, C.J., Cari, E.L., Sandoval, J. et al. Control of Murine Primordial Follicle Growth Activation by IκB/NFκB Signaling. Reprod. Sci. 27, 2063–2074 (2020). https://doi.org/10.1007/s43032-020-00225-3

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