Loss of NTRK2/KISS1R signaling in oocytes causes premature Ovarian failure

Mauricio D. Dorfman, Cecilia Garcia-Rudaz, Zefora Alderman, Bredford Kerr, Alejandro Lomniczi, Gregory A. Dissen, Juan Manuel Castellano, David Garcia-Galiano, Francisco Gaytan, Baoji Xu, Manuel Tena-Sempere, Sergio R. Ojeda

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    41 Scopus citations

    Abstract

    Neurotrophins (NTs), once believed to be neural-specific trophic factors, are now known to also provide developmental cuestonon-neural cells. Inthe ovary, NTs contribute to both the formation and development of follicles. Here we show that oocyte-specific deletion of the Ntrk2 gene that encodes the NTRK2 receptor (NTRK2) for neurotrophin-4/5 and brain-derived neurotrophic factor (BDNF) results in post-pubertal oocyte death, loss of follicular organization, and early adulthood infertility. Oocytes lacking NTRK2 do not respond to gonadotropins with activation of phospha-tidylinositol 3-kinase (PI3K)-AKT-mediated signaling. Before puberty, oocytes only express a truncated NTRK2 form (NTRK2. T1), but at puberty full-length (NTRK2. FL) receptors are rapidly induced by the preovulatory gonadotropin surge. A cell line expressing both NTRK2. T1 and the kisspeptin receptor (KISS1R) responds to BDNF stimulation with activation of Ntrk2 expression only if kiss-peptin is present. This suggests that BDNF and kisspeptin that are produced by granulosa cells (GCs) of periovulatory follicles act in concert to mediate the effect of gonadotropins on Ntrk2 expression in oocytes. In keeping with this finding, the oocytes of NTRK2-intact mice fail to respond to go-nadotropins with increased Ntrk2 expression in the absence of KISS1R. Our results demonstrate that the preovulatory gonadotropin surge promotes oocyte survival at the onset of reproductive cyclicity by inducing oocyte expression of NTRK2. FL receptors that set in motion an AKT-mediated survival pathway. They also suggest that gonadotropins activate NTRK2. FL expression via a dual communication pathway involving BDNF and kisspeptin produced in GCs and their respective receptors NTRK2. T1 and KISS1R expressed in oocytes.

    Original languageEnglish (US)
    Pages (from-to)3098-3111
    Number of pages14
    JournalEndocrinology
    Volume155
    Issue number8
    DOIs
    StatePublished - Aug 2014

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    ASJC Scopus subject areas

    • Endocrinology

    Cite this

    Dorfman, M. D., Garcia-Rudaz, C., Alderman, Z., Kerr, B., Lomniczi, A., Dissen, G. A., Castellano, J. M., Garcia-Galiano, D., Gaytan, F., Xu, B., Tena-Sempere, M., & Ojeda, S. R. (2014). Loss of NTRK2/KISS1R signaling in oocytes causes premature Ovarian failure. Endocrinology, 155(8), 3098-3111. https://doi.org/10.1210/en.2014-1111