Loss of Ntrk2/Kiss1r Signaling in Oocytes Causes Premature Ovarian Failure

Abstract

Neurotrophins (NTs), once believed to be neural-specific trophic factors, are now known to also provide developmental cues to non-neural cells. In the 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 phosphatidylinositol 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 kisspeptin 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 gonadotropins 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.

Rola sygnalizacji kisspeptyny w osi podwzgórze–przysadka–nadnercza — aktualna perspektywa

“…Similar results were observed in indomethacintreated rats and photo-inhibited hamsters [155,157]. Additionally, recent studies on kiss1r heterozygous and knockout mice models further provide strong evidence in favour of the direct role of kisspeptins in the ovary by revealing that the loss of one kiss1r allele resulted in premature ovarian failure and loss of both kiss1r alleles blocked maturation of ovarian follicles and ovulation, which could not be rescued by gonadotrophins administration [159][160][161]. It has also been suggested that localised kisspeptin signalling is crucial for endometrial decidualisation and embryo implantation.…”

Intra‐follicular kisspeptin levels are related to oocyte maturation and gonadal hormones in patients who are undergoing assisted reproductive technology

“…In rat studies, it is known that the expression level of KiSS‐1 messenger RNA in the immature ovary is low and it is increased with pregnant‐mare serum gonadotropin–hCG stimulation . In addition, it has been reported that the signal of neurotrophin via the NTRK2 receptor, which is indispensable for the maturation of oocytes, depends on the signal of the kisspeptin receptor . In addition to the results of this experiment, it can be said that these are all related to egg maturation and kisspeptin.…”

“…8 In addition, it has been reported that the signal of neurotrophin via the NTRK2 receptor, which is indispensable for the maturation of oocytes, depends on the signal of the kisspeptin receptor. 31 In addition to the results of this experiment, it can be said that these are all related to egg maturation and kisspeptin. Many of the mechanisms are not yet understood, but now that kisspeptin is known to be present in the follicular fluid, it will be possible to investigate in detail the kisspeptin concentrations in the follicular fluid and egg maturity in the future, which could help to elucidate the function of kisspeptin in the ovary.…”

Kisspeptin cell-specific PI3K signaling regulates hypothalamic kisspeptin expression and participates in the regulation of female fertility

“…Activation of PI3K can also phosphorylate ER␣ on specific residues to regulate its transcriptional activity and stability (10). Alternatively, kisspeptin is also expressed in the ovary, oviduct, and uterus (9,26,35). PI3K may be part of the intracellular signaling mechanisms mediating the activation of kisspeptin neurons during the E 2 -induced LH surge.…”