title: Estrogen induced changes in uterine brain-derived neurotrophic factor and its receptors.
abstract: OBJECTIVE
  Are brain-derived neurotrophic factor (BDNF) and its receptors, NTRK2, NGFR and SORT1, regulated by ovarian steroids in the uterus?
  
  
  CONCLUSIONS
  BDNF and its low affinity receptor, nerve growth factor receptor (NGFR), are regulated by estradiol in the uterus.
  
  
  BACKGROUND
  Recent studies have revealed a central role for neurotrophins in placental development, endometrial stem cell neurogenesis, endometrial carcinoma and endometriosis. Complex signaling pathways involving BDNF and its receptors are regulated by ovarian hormones in the brain, however their expression and regulation in the uterus is poorly defined.
  
  
  METHODS
  This experimental animal study involved a total of 80 mice.
  
  
  METHODS
  Female C57BL/6 mice (n = 50) were monitored daily for estrous cycle stage, and uterine horns were collected. A second group of mice (n = 30) were ovariectomized and given estradiol, progesterone, estradiol + progesterone, or saline for 4 days. Uterine expression of BDNF and its receptors were quantified by real-time PCR and western blot, and localized using immunohistochemistry.
  
  
  RESULTS
  During the estrous cycle, expression of BDNF, NTRK2 and SORT1 remained constant, while NGFR declined 11-fold from pro-estrus through to diestrus (P = 0.005). In ovariectomized mice, estradiol treatment increased uterine expression of mature BDNF greater than 6-fold (P = 0.013, 25 kDa; P = 0.003, 27 kDa), pro-BDNF 5-fold (P = 0.041, 37 kDa band; P = 0.046, 40 kDa band), and NGFR 5-fold (P < 0.001) when compared with other treatments. NTRK2 and SORT1 were unaffected by ovarian hormones. NGFR was primarily localized in epithelial cells in mice in diestrus or in ovariectomized mice treated with progesterone (P ≤ 0.001; P ≤ 0.001, respectively). In contrast, NGFR switched to a stromal localization in ovariectomized mice administered estradiol (P = 0.002).
  
  
  CONCLUSIONS
  This study was performed in one only species.
  
  
  CONCLUSIONS
  Results of this study demonstrate the uterine regulation of BDNF and NGFR by estradiol, and highlight the striking difference between hormone exposure during the estrous cycle and daily estradiol exposure after ovariectomy on neurotrophin expression in the uterus. The results also show the spatial regulation of NGFR in the uterus in response to ovarian hormones. Sustained estrogen exposure, as seen in estrogen-dependent disease, may alter the delicate neurotrophin balance and inappropriately activate potent BDNF-NTRK2 pathways which are capable of contributing to endometrial pathology.
  
  
  BACKGROUND
  This study was supported by the Canadian Institutes of Health Research (CIHR) (W.G.F.), a NSERC Discovery Grant (W.G.F.), and a Vanier Canada Graduate Scholarship-CIHR (J.M.W.). J.M.W. is a member of the CIHR sponsored Reproduction and Early Development in Health training program. The authors declare no conflicts of interest.
authors: Department of Obstetrics and Gynecology, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
authors: Jocelyn M
authors: JM
authors: Wessels
authors: Department of Obstetrics and Gynecology, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
authors: Nicholas A
authors: NA
authors: Leyland
authors: Department of Reproductive Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors: Sanjay K
authors: SK
authors: Agarwal
authors: Department of Obstetrics and Gynecology, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada fosterw@mcmaster.ca.
authors: Warren G
authors: WG
authors: Foster
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D004958:Estradiol / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D004971:Estrus; D005260:Female; D005786:Gene Expression Regulation; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000378:metabolism; D010052:Ovariectomy; D010053:Ovary / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D013256:Steroids / Q000378:metabolism; D014599:Uterus / Q000378:metabolism*; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D019208:Brain-Derived Neurotrophic Factor; D004958:Estradiol; D004967:Estrogens; D008562:Membrane Glycoproteins; D009414:Nerve Growth Factors; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; D013256:Steroids; D000099183:Sortilin; C064371:Ntrk2 protein, mouse
keywords: BDNF; NGFR; NTRK2; estrogen; sortilin