Control of Murine Primordial Follicle Growth Activation by IκB/NFκB Signaling
| Autor: | Joshua Johnson, Peter Ka Sam, Elise S. Bales, Jeryl Sandoval, Clyde J. Wright, Evelyn Llerena Cari, Alex J. Polotsky, Miguel A Zarate, Amanda N. Kallen |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
P50 Ovary Article 03 medical and health sciences 0302 clinical medicine NF-KappaB Inhibitor alpha Ovarian Follicle medicine Animals Receptor Transcription factor Mice Inbred ICR 030219 obstetrics & reproductive medicine Kinase Chemistry Tumor Necrosis Factor-alpha NF-kappa B Obstetrics and Gynecology NF-kappa B p50 Subunit Cell biology IκBα 030104 developmental biology medicine.anatomical_structure Tumor necrosis factor alpha Female I-kappa B Proteins Folliculogenesis Signal Transduction |
| Zdroj: | Reprod Sci |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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