title: 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.
authors.affiliation: Division of Neuroscience (M.D.D., C.G.-R., Z.A., B.K., A.L., G.A.D., J.M.C., S.R.O.), Oregon National Primate Research Center/Oregon Health and Science University, Beaverton, Oregon 97006; Department of Cell Biology, Physiology and Immunology (D.G.-G., F.G., M.T.-S.), University of Córdoba; Centro de Investigacion Biomedica en Red (CIBER) Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III; and Instituto Maimónides de Investigaciones Biomédicas/Hospital Universitario Reina Sofia, Cordoba, Spain 14004; and Department of Pharmacology and Physiology (B.X.), Georgetown University Medical Center, Washington DC 20057.
authors.forename: Mauricio D
authors.initials: MD
authors.lastname: Dorfman
authors.forename: Cecilia
authors.initials: C
authors.lastname: Garcia-Rudaz
authors.forename: Zefora
authors.initials: Z
authors.lastname: Alderman
authors.forename: Bredford
authors.initials: B
authors.lastname: Kerr
authors.forename: Alejandro
authors.initials: A
authors.lastname: Lomniczi
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Dissen
authors.forename: Juan Manuel
authors.initials: JM
authors.lastname: Castellano
authors.forename: David
authors.initials: D
authors.lastname: Garcia-Galiano
authors.forename: Francisco
authors.initials: F
authors.lastname: Gaytan
authors.forename: Baoji
authors.initials: B
authors.lastname: Xu
authors.forename: Manuel
authors.initials: M
authors.lastname: Tena-Sempere
authors.forename: Sergio R
authors.initials: SR
authors.lastname: Ojeda
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D005260:Female; D006062:Gonadotropins / Q000502:physiology; D007247:Infertility, Female / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009865:Oocytes / Q000378:metabolism*; D010053:Ovary / Q000378:metabolism*; D016649:Primary Ovarian Insufficiency / Q000209:etiology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D000074502:Receptors, Kisspeptin-1; D020813:Receptor, trkB
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D006062:Gonadotropins; D008562:Membrane Glycoproteins; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; C492248:Kiss1r protein, mouse; C064371:Ntrk2 protein, mouse; D020813:Receptor, trkB