TY - JOUR
T1 - Loss of NTRK2/KISS1R signaling in oocytes causes premature Ovarian failure
AU - Dorfman, Mauricio D.
AU - Garcia-Rudaz, Cecilia
AU - Alderman, Zefora
AU - Kerr, Bredford
AU - Lomniczi, Alejandro
AU - Dissen, Gregory A.
AU - Castellano, Juan Manuel
AU - Garcia-Galiano, David
AU - Gaytan, Francisco
AU - Xu, Baoji
AU - Tena-Sempere, Manuel
AU - Ojeda, Sergio R.
PY - 2014/8
Y1 - 2014/8
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84905046890&partnerID=8YFLogxK
U2 - 10.1210/en.2014-1111
DO - 10.1210/en.2014-1111
M3 - Article
C2 - 24877631
AN - SCOPUS:84905046890
SN - 0013-7227
VL - 155
SP - 3098
EP - 3111
JO - Endocrinology
JF - Endocrinology
IS - 8
ER -