PMID- 24877631
OWN - NLM
STAT- MEDLINE
DCOM- 20140919
LR  - 20211021
IS  - 1945-7170 (Electronic)
IS  - 0013-7227 (Print)
IS  - 0013-7227 (Linking)
VI  - 155
IP  - 8
DP  - 2014 Aug
TI  - Loss of Ntrk2/Kiss1r signaling in oocytes causes premature ovarian failure.
PG  - 3098-111
LID - 10.1210/en.2014-1111 [doi]
AB  - 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.
FAU - Dorfman, Mauricio D
AU  - Dorfman MD
AD  - 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 Cordoba; Centro de 
      Investigacion Biomedica en Red (CIBER) Fisiopatologia de la Obesidad y Nutricion, 
      Instituto de Salud Carlos III; and Instituto Maimonides de Investigaciones 
      Biomedicas/Hospital Universitario Reina Sofia, Cordoba, Spain 14004; and 
      Department of Pharmacology and Physiology (B.X.), Georgetown University Medical 
      Center, Washington DC 20057.
FAU - Garcia-Rudaz, Cecilia
AU  - Garcia-Rudaz C
FAU - Alderman, Zefora
AU  - Alderman Z
FAU - Kerr, Bredford
AU  - Kerr B
FAU - Lomniczi, Alejandro
AU  - Lomniczi A
FAU - Dissen, Gregory A
AU  - Dissen GA
FAU - Castellano, Juan Manuel
AU  - Castellano JM
FAU - Garcia-Galiano, David
AU  - Garcia-Galiano D
FAU - Gaytan, Francisco
AU  - Gaytan F
FAU - Xu, Baoji
AU  - Xu B
FAU - Tena-Sempere, Manuel
AU  - Tena-Sempere M
FAU - Ojeda, Sergio R
AU  - Ojeda SR
LA  - eng
GR  - P51 OD011092/OD/NIH HHS/United States
GR  - P51 RR000163/RR/NCRR NIH HHS/United States
GR  - HD24870/HD/NICHD NIH HHS/United States
GR  - 8P51OD011092/OD/NIH HHS/United States
GR  - R01 HD024870/HD/NICHD NIH HHS/United States
GR  - HD24870-ARRA/HD/NICHD NIH HHS/United States
GR  - R01 HD084542/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, American Recovery and Reinvestment Act
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140530
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Gonadotropins)
RN  - 0 (Kiss1r protein, mouse)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - 0 (Receptors, Kisspeptin-1)
RN  - EC 2.7.10.1 (Ntrk2 protein, mouse)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
CIN - Endocrinology. 2014 Aug;155(8):2751-3. PMID: 25036649
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/metabolism
MH  - Female
MH  - Gonadotropins/physiology
MH  - Infertility, Female/genetics
MH  - Male
MH  - Membrane Glycoproteins/genetics/*metabolism
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Oocytes/*metabolism
MH  - Ovary/*metabolism
MH  - Primary Ovarian Insufficiency/*etiology
MH  - Protein-Tyrosine Kinases/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Receptors, G-Protein-Coupled/*metabolism
MH  - Receptors, Kisspeptin-1
PMC - PMC4097998
EDAT- 2014/06/01 06:00
MHDA- 2014/09/23 06:00
PMCR- 2015/08/01
CRDT- 2014/06/01 06:00
PHST- 2014/06/01 06:00 [entrez]
PHST- 2014/06/01 06:00 [pubmed]
PHST- 2014/09/23 06:00 [medline]
PHST- 2015/08/01 00:00 [pmc-release]
AID - EN-14-1111 [pii]
AID - 10.1210/en.2014-1111 [doi]
PST - ppublish
SO  - Endocrinology. 2014 Aug;155(8):3098-111. doi: 10.1210/en.2014-1111. Epub 2014 May 
      30.