| brain derived neurotrophic factor | OKDB#: 1037 |
| Symbols: | BDNF | Species: | human | ||
| Synonyms: | ANON2, BULN2 | Locus: | 11p14.1 in Homo sapiens |
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OMIM
Entrez Gene
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| General Comment |
In addition to nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) has been purified and shown in vivo to reduce the amount of
naturally occurring neuronal cell death in portions of the peripheral nervous system. NGF and BDNF show
considerable amino acid and nucleotide sequence similarity.
NCBI Summary: This gene encodes a member of the nerve growth factor family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature protein. Binding of this protein to its cognate receptor promotes neuronal survival in the adult brain. Expression of this gene is reduced in Alzheimer's, Parkinson's, and Huntington's disease patients. This gene may play a role in the regulation of the stress response and in the biology of mood disorders. [provided by RefSeq, Nov 2015] |
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| General function | Ligand, Growth factor | ||||
| Comment | Brain-derived neurotrophic factor from follicular fluid is positively associated with rate of mature ooocytes collected and cleavage rate in intracytoplasmic sperm injection patients. Wang X et al. PURPOSE: The aim of the study was to evaluate the correlation between BDNF and oocyte maturation and to verify whether BDNF could predict in vitro fertilization (IVF) outcome. METHODS: The follicle fluid (FF) for BDNF, E(2) and P assay were obtained from 59 patients undergoing intracytoplasmic sperm injection (ICSI). The women were divided into two groups by pregnancy outcome and their clinical and lab data were compared. And the correlation of BDNF with E(2), P, age, and IVF data were analyzed. RESULTS: Positive correlation was observed between BDNF and E(2) concentration in FF. BDNF was positively correlated with the rate of mature oocytes collected and cleavage rate. CONCLUSIONS: The BDNF in FF could not predict IVF outcome, but BDNF in FF might play an important role in the maturation of oocyte and development of oocyte into preimplantation embryo. Brain-derived neurotrophic factor plasma variation during the different phases of the menstrual cycle in women with premenstrual syndrome. Cubeddu A et al. Premenstrual syndrome (PMS) is characterized by a cluster of psychological and somatic symptoms that begin during the late luteal phase of the menstrual cycle and disappear after the onset of menses. Since PMS might be caused by an alteration in the cyclical hormonal modifications and ovarian steroids are directly involved in the regulation of mood, affective and cognitive functions and influence neurotrophins expression, in particular the brain-derived neurotrophic factor (BDNF), we aimed to evaluate whether plasma BDNF levels in women with PMS differ from those of normally menstruating women without PMS. Sixty-two women were divided into two groups: one group of women (n=35) with PMS and one group (n=27) composed by normally menstruating women. Plasma samples were collected at day 7 (follicular phase) and day 21 (luteal phase) of the menstrual cycle. Plasma BDNF of the control group significantly increased (p<0.001) from the follicular phase (402.90?74.41pg/ml) to the luteal phase (1098.79?146.49pg/ml). On the other hand, in the PMS group plasma BDNF levels significantly decreased (p<0.001) from the follicular phase (412.45?78.35pg/ml) to the luteal phase (233.03?75.46pg/ml) Luteal BDNF levels of the PMS women were significantly lower than those of the control group (p<0.001). In women with PMS, plasma BDNF followed a decreasing trend during the ovarian cycle, in opposition to the increasing trend observed in women without PMS. The lower luteal BDNF levels of the PMS women might be a consequence of an altered hormonal response and might play a role in the onset of the symptoms PMS related. | ||||
| Cellular localization | Secreted | ||||
| Comment | |||||
| Ovarian function |
Follicle development, Initiation of primordial follicle growth, Primary follicle growth, Cumulus expansion, Steroid metabolism, Luteinization, Oogenesis, Oocyte maturation, Early embryo development
, First polar body extrusion |
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| Comment | Brain-derived neurotrophic factor promotes proliferation and progesterone synthesis in bovine granulosa cells. Chen S et al. (2018) Brain-derived neurotrophic factor (BDNF) is involved in regulating the growth of ovarian follicles, maturation of the oocyte, and development of the early embryo through its receptor, tyrosine kinase receptor B (TrkB). However, it is still unclear as to how BDNF influences proliferation and steroidogenesis of bovine granulosa cells (GCs). In this paper, we confirmed that BDNF and TrkB were expressed in bovine GCs, and that proliferation and steroidogenesis by bovine GCs were reduced by knockdown of BDNF or inhibition of TrkB. With respect to GC proliferation, BDNF enhanced cellular viability and the percentage of cells in the S phase. BDNF also activated both protein kinase B (PKB, also known as AKT) and the extracellular signal-regulated protein kinase 1/2 (ERK1/2)-signaling pathway. Through the AKT-signaling pathway, BDNF increased the expression of proliferation-related genes, including cyclin A1 (CCNA1), cyclin E2 (CCNE2), cyclin D1 (CCND1), and cyclin-dependent kinase 1 (CDK1). However, through the ERK1/2 signaling pathway, BDNF only increased the expression of CCNA1 and CCNE2. Regarding steroidogenesis by bovine GCs, BDNF promoted progesterone (P 4 ) synthesis, but had no effect on estradiol; it also activated the AKT-signaling pathway and increased the expression of steroidogenesis-related genes, including steroidogenic acute regulatory protein (STAR) and hydroxy-δ-5-steroid dehydrogenase, 3β- and steroid δ-isomerase 1 (HSD3B1). In summary, our data are the first to show that BDNF promotes the proliferation of bovine GCs through TrkB-AKT and ERK1/2 signaling pathways and increases P4 synthesis by bovine GCs through the TrkB-AKT signaling pathway.//////////////////Brain-derived neurotrophic factor promotes human granulosa-like tumor cell steroidogenesis and proliferation by activating the FSH receptor-mediated signaling pathway. Xie M et al. (2017) Brain-derived neurotrophic factor (BDNF) and FSH receptor (FSHR) are expressed in ovarian granulosa cells, and play important roles in regulating follicle growth and oocyte maturation. Studies have linked the BDNF-associated signaling pathway to FSHR mRNA expression in the regulation of follicle development, but the mechanisms remain unknown. In the current study, we found that BDNF stimulated the secretion of estradiol and progesterone, and increased the proliferation of KGN cells (human granulosa-like tumor cell line). BDNF treatment also increased phosphorylated and ubiquitinated FSHR, and activated cAMP/PKA/CREB signaling pathway. Moreover, inhibition of BDNF expression by siRNA markedly reduced the estradiol secretion and down-regulated FSHR, aromatase and phosphorylated CREB; meanwhile, FSH treatment partly alleviated the effects of BDNF siRNA on KGN cells. These findings suggested that BDNF modulates graunlosa cell functions and the action probably mediated by FSHR-coupled signaling pathway, to affect aromatase-mediated steroidogenesis. These results provide an alternative target to optimize ovarian granulosa cell function.////////////////// Neurotrophin NT3 Promotes Ovarian Primordial to Primary Follicle Transition. Nilsson E et al. Neurotrophins are growth factors that are known to have a role in promoting cell survival and differentiation. The focus of the current study is to examine the role of neurotrophins in regulating ovarian primordial follicle development. Ovaries from four-day old rats were placed into organ culture and cultured for ten days in the absence or presence of Neurotrophin-3 (NT3), Brain-Derived Neurotrophic Factor (BDNF) or Nerve Growth Factor (NGF). Treatment of ovaries with NT3 resulted in a significant (p<0.01) increase in primordial follicle development (i.e. primordial to primary follicle transition). Treatment with BDNF at high doses of 100-250 ng/ml also significantly (p<0.01) increased primordial follicle development, but NGF had no effect. Immunohistochemistry studies determined that NT3 was present in granulosa cells, interstitial tissue, and in the oocytes of primordial and primary follicles. The NT3 receptor TrkC was present in oocytes at all stages of development. Analysis of ovaries that contain predominantly primordial follicles demonstrated the transcripts for NT3, TrkC, NGF and the BDNF/NT4 receptor TrkB are expressed, while BDNF, NT4 and the NGF receptor TrkA are not detectable. Inhibition of the TrkC receptor with the tyrphostin AG879 resulted in oocyte death and a significant (p<0.01) reduction in follicle pool size. Inhibition of the Trk receptors with K252a slowed primordial to primary follicle transition. A microarray analysis demonstrated a small number of genes were found to be differentially expressed after NT3 treatment. Observations indicate that the neurotrophin NT3, acting through the TrkC receptor in oocytes, promotes the primordial to primary follicle transition. Ovarian brain-derived neurotrophic factor (BDNF) promotes the development of oocytes into preimplantation embryos Kawamura K, et al . Optimal development of fertilized eggs into preimplantation embryos is essential for reproduction. Although mammalian oocytes ovulated after luteinizing hormone (LH) stimulation can be fertilized and promoted into early embryos in vitro, little is known about ovarian factors important for the conditioning of eggs for early embryo development. Because LH interacts only with ovarian somatic cells, its potential regulation of oocyte functions is presumably mediated by local paracrine factors. We performed DNA microarray analyses of ovarian transcripts and identified brain-derived neurotrophic factor (BDNF) secreted by granulosa and cumulus cells as an ovarian factor stimulated by the preovulatory LH surge. Ovarian BDNF acts on TrkB receptors expressed exclusively in oocytes to enhance first polar body extrusion of oocytes and to promote the in vitro development of zygotes into preimplantation embryos. Furthermore, in vivo treatment with a Trk receptor inhibitor suppressed first polar body extrusion and the progression of zygotes into blastocysts. Thus, ovarian BDNF is important to nuclear and cytoplasmic maturation of the oocyte, which is essential for successful oocyte development into preimplantation embryos. Treatment with BDNF could condition the cultured oocytes for optimal progression into the totipotent blastocysts. ////////Dose-dependent embryotrophic effect of recombinant granulocyte-macrophage colony-stimulating factor and brain-derived neurotrophic factor in culture medium for mouse preimplantation embryo. Kim JH 2014 et al. OBJECTIVE To evaluate the dose effect of recombinant mouse granulocyte-macrophage colony-stimulating factor (rmGM-CSF) or brain-derived neurotrophic factor (BDNF) in culture medium on the development of in vitro fertilized mouse embryos. METHODS Mature oocytes were retrieved from superovulated female BDF1 mice and inseminated by sperm from male BDF1 mice. On day 1, two-cell stage embryos were divided and cultured until day 5 in the embryo maintenance medium supplemented with 0, 1, 2, 5, or 10 ng/mL of rmGM-CSF or supplemented with 0, 5, 10, or 20 ng/mL of BDNF. Blastocyst formation rate and their cell numbers were assessed. RESULTS The blastocyst formation rate and the total cell count in blastocyst was similar in all the rmGM-CSF treatment groups when compared with the control. However, the blastocyst formation rate and the total cell count was significantly higher in the group supplemented with 10 ng/mL of BDNF compared with the control (63.9%, 45.811.5 vs. 52.3%, 38.06.8; P<0.05, respectively). CONCLUSION Supplementation of 10 ng/mL of BDNF enhanced the developmental potential of mouse preimplantation embryos, but supplementation of rmGM-CSF did not. ///////////////////////// Effects of brain-derived neurotrophic factor on oocyte maturation and embryonic development in a rat model of polycystic ovary syndrome. Zhang Q et al. (2015) Brain-derived neurotrophic factor (BDNF) is expressed extensively in the mammalian female reproductive system and has been implicated in the development of follicles and oocytes. However, BDNF expression patterns in the ovary and its effects on oocyte maturation and embryonic development in polycystic ovary syndrome (PCOS) have not been established. In the present study, we established a PCOS model by treating the rats with insulin and human chorionic gonadotropin (hCG). Rats treated with insulin + hCG had heavier bodyweight and ovarian weight, higher circulating concentrations of luteinising hormone (LH) and testosterone (T), and greater homeostatic model assessment of insulin resistance (HOMA-IR) values compared with control rats (P < 0.05). BDNF and its receptor tyrosine kinase type B (TrkB) were located in cyst walls, granulosa and theca cells, and BDNF protein levels were lower in ovaries of insulin + hCG-treated rats (P < 0.05). The rate of oocyte maturation and formation of blastocysts and morulae was greatest in rats treated with 5 ng mL-1 BDNF (P < 0.05) compared to other BDNF groups (1 and 10 ng mL-1) and the control. The control rats were also PCOS rats and were treated without BDNF. There were no significant differences in the rate of germinal vesicle breakdown (GVBD) and fertilisation among the various treatment groups (1, 5 and 10 ng mL-1) and the control group (P > 0.05). The results indicate that in vitro treatment with an appropriate concentration of BDNF not only promotes oocyte maturation, but also rescues embryonic development in rats treated with insulin + hCG as a model of PCOS.////////////////// Brain-derived neurotrophin factor inhibits steroid biosynthesis by human granulosa-lutein cells. Promotion of human early embryonic development and blastocyst outgrowth in vitro using autocrine/paracrine growth factors. Kawamura K et al. Studies using animal models demonstrated the importance of autocrine/paracrine factors secreted by preimplantation embryos and reproductive tracts for embryonic development and implantation. Although in vitro fertilization-embryo transfer (IVF-ET) is an established procedure, there is no evidence that present culture conditions are optimal for human early embryonic development. In this study, key polypeptide ligands known to be important for early embryonic development in animal models were tested for their ability to improve human early embryo development and blastocyst outgrowth in vitro. We confirmed the expression of key ligand/receptor pairs in cleavage embryos derived from discarded human tri-pronuclear zygotes and in human endometrium. Combined treatment with key embryonic growth factors (brain-derived neurotrophic factor, colony-stimulating factor, epidermal growth factor, granulocyte macrophage colony-stimulating factor, insulin-like growth factor-1, glial cell-line derived neurotrophic factor, and artemin) in serum-free media promoted >2.5-fold the development of tri-pronuclear zygotes to blastocysts. For normally fertilized embryos, day 3 surplus embryos cultured individually with the key growth factors showed >3-fold increases in the development of 6-8 cell stage embryos to blastocysts and >7-fold increase in the proportion of high quality blastocysts based on Gardner's criteria. Growth factor treatment also led to a 2-fold promotion of blastocyst outgrowth in vitro when day 7 surplus hatching blastocysts were used. When failed-to-be-fertilized oocytes were used to perform somatic cell nuclear transfer (SCNT) using fibroblasts as donor karyoplasts, inclusion of growth factors increased the progression of reconstructed SCNT embryos to >4-cell stage embryos. Growth factor supplementation of serum-free cultures could promote optimal early embryonic development and implantation in IVF-ET and SCNT procedures. This approach is valuable for infertility treatment and future derivation of patient-specific embryonic stem cells. Chen W, et al . OBJECTIVE: To study the effect of brain-derived neurotrophin factor (BDNF) on the synthesis of estradiol and progesterone in human granulose-lutein cells (HGLCs) and the expression of steroidogenic acute regulatory factor (STAR) mRNA. METHODS: HGLCs were obtained from infertile women undergoing ovulation induction for fertilization-embryo transfer (IVF-ET) for male or tubal factors. HGLCs were cultured in serum-free media 199 for 24 h and treated by BDNF at 25, 50 and 100 ng/ml. Radio immunoassay (RIA) was used to examine the concentration of estradiol and progesterone, and reverse transcriptional PCR (RT-PCR) employed to detect the expression of STAR mRNA after treatment with BDNF at the concentrations of 25, 50 and 100 ng/ml. RESULTS: BDNF significantly inhibited the production of progesterone (P(4)) in the culture media of HGLCs in a dose-dependent manner. BDNF did not change the level of 17beta-estradiol (E(2)), but decreased the expression of STAR mRNA dose-dependently. CONCLUSIONS: BDNF can inhibit the synthesis of P(4) in HGLCs and regulate ovarian steroidogenesis. BDNF may inhibit HGLCs from producing P(4) by decreasing the transcription level of STAR gene in human ovary, and plays an important role in luteal regression. Brain-derived neurotrophic factor promotes bovine oocyte cytoplasmic competence for embryo development Martins da Silva SJ,et al . The ability of an oocyte to support early embryonic development requires both nuclear and cytoplasmic maturation. We have investigated the effects of brain-derived neurotrophic factor (BDNF) on maturation of the bovine oocyte and embryo development after parthenogenetic activation. By RT-PCR and immunohistochemistry, cumulus and oocytes were shown to express mRNA and protein for BDNF and the p75 common neurotrophin receptor. However, mRNA for the BDNF-specific full length and truncated isoforms of the TrkB receptor are only detected in cumulus, suggesting that oocytes and cumulus differ in their capacity to respond to neurotrophin signalling. In in vitro maturation experiments, the proportion of cumulus oocyte complexes maturing to metaphase II was not altered by BDNF in groups lacking fetal calf serum (FCS), but was significantly lower than the positive control containing 10% FCS (P < 0.01). However, after maturation, the proportion of parthenogenetically activated oocytes forming blastocysts was highest for 10 ng/ml BDNF (24%, n = 95) followed by 100 ng/ml BDNF (18%, n = 91) and 10% FCS (15%, n = 103), which in turn were greater than no serum (10%, n = 83; P < 0.01). Maturation in the presence of a BDNF blocking antibody resulted in a blastocyst yield that was comparable to the absence of serum, and lower than in the presence of BDNF (P < 0.01). Similar effects on progression to metaphase II and blastocyst formation were observed using oocytes matured without cumulus. Together, these results provide the first evidence for a role for neurotrophins in promoting oocyte cytoplasmic competence to support embryonic development, despite being insufficient in the absence of serum to enhance nuclear maturation. Beneficial effects of brain-derived neurotropic factor on in vitro maturation of porcine oocytes. Lee E et al. In an effort to improve the quality of in vitro produced porcine embryos, we investigated the effect of brain-derived neurotropic factor (BDNF), a neurotropin family member, on in vitro maturation (IVM) of porcine oocytes. The expression of BDNF and truncated isoforms of its receptor, tyrosine kinase B (TrkB), and p75 common neurotropin receptor was detected in both follicular cells and metaphase-I stage oocytes by RT-PCR. However, mRNA of full-length TrkB was not found in oocytes although it was detected in follicular cells. The expression pattern of BDNF and TrkB was confirmed by immunohistochemistry. Supplementation with BDNF (30 ng/ml) during IVM significantly (P < 0.05) increased the first polar body extrusion and glutathione levels in oocytes, whereas the effect of BDNF on nuclear maturation was diminished when gonadotropin and epidermal growth factor (EGF) were added to the culture media. However, treatment with BDNF (30 ng/ml) along with EGF (10 ng/ml) in the presence of gonadotropin significantly (P < 0.05) increased the developmental competence of oocytes to the blastocyst stage after both in vitro fertilization (IVF; 29.1% when compared with control, 15.6%) and somatic cell nuclear transfer (SCNT; 13.6% when compared with control, 3%). This appeared to reflect a stimulatory interaction between BDNF and EGF to enhance the cytoplasmic maturation of oocytes to support successful preimplantation development. In conclusion, BDNFenhanced nuclearand cytoplasmic maturation of oocytes by autocrine and/or paracrine signals. Also, when used together with EGF, BDNF increased the developmental potency of embryos after IVF and SCNT, demonstrating an improved in vitro production protocol for porcine oocytes. The effects of brain-derived neurotrophic factor and metformin on in vitro developmental competence of bovine oocytes. Hong SG et al. SummaryBrain-derived neurotrophic factor (BDNF) signalling via tyrosine kinase B receptors may play an important role in ovarian development and function. It has been reported that metformin elevates the activity of Tyrosine kinase receptors and may amplify BDNF signalling. The objective of this study was to investigate the effect of BDNF during in vitro maturation (IVM) and/or in vitro culture (IVC) (Experiment 1), and to evaluate the collaborative effect of BDNF and metformin treatment on the developmental competence of bovine in vitro fertilized (IVF) embryos (Experiment 2). In Experiment 1, BDNF, which was added to our previously established IVM systems, significantly increased the proportions of MII oocytes at both 10 ng/ml (86.7%) and 100 ng/ml (85.4%) compared with the control (64.0%). However, there was no statistically significant difference in blastocyst development between the control or BDNF-supplemented groups. In Experiment 2, in order to investigate the effect of BDNF (10 ng/ml) and/or metformin (10-5 M) per se, TCM-199 without serum and hormones was used as the control IVM medium. The BDNF (48.3%) and BDNF plus metformin (56.5%) significantly enhanced the proportions of MII oocytes compared with the control (34.4%). Although, BDNF or metformin alone had no effect in embryo development, BDNF plus metformin significantly improved early embryo development to the 8-16-cell stage compared with the control (16.5 vs. 5.5%). In conclusion, the combination of BDNF and metformin may have a collaborative effect during the IVM period. These results could further contribute to the establishment of a more efficient bovine in vitro embryo production system. Brain-derived neurotrophic factor is a regulator of human oocyte maturation and early embryo development. Anderson RA et al. OBJECTIVE: To investigate a role for brain-derived neurotrophic factor (BDNF) in human oocyte maturation. DESIGN: Prospective study. SETTING: Research institute. PATIENTS: Women undergoing laparoscopic sterilization. INTERVENTION(S): Small antral follicle cumulus-oocyte complexes (COCs) were matured in vitro (IVM) to metaphase II (MII) in media with hormones (H; FSH, LH, E(2)), serum replacement (SR), BDNF, or blocking antibodies to BDNF (BDNF/AB and TrkB/Fc), and activated. MAIN OUTCOME MEASURE(S): The COCs were analyzed for expression of neurotrophin ligands/receptors and cumulus genes (HAS2, TNFAlP6, PTGS2, GREM1) by reverse transcription-polymerase chain reaction (RT-PCR), cumulus expansion, maturation to MII, and parthenogenetic embryo development. RESULT(S): The BDNF and truncated TrkB receptor were expressed in cumulus and mature oocytes. There was no difference in MII yields after IVM in control (H + SR) versus H + BDNF, H + SR + BDNF, or BDNF + SR media. However, both BDNF/AB and TrkB/Fc improved MII yields. After activation, normal cleavage was highest in H + SR (38%), whereas blocking antibodies yielded the highest abnormal cleavage (BDNF/AB 68%; TrkB/Fc 57%). Failure to cleave was highest in H + BDNF + SR (92%). Only H + SR yielded morulae/blastocysts (6%). Expression of GREM1 in cumulus increased after IVM in H + BDNF versus H + SR or in vivo maturation. CONCLUSION(S): The BDNF signaling within COCs influences oocyte maturation and early embryogenesis. The role of brain-derived neurotrophic factor in mouse oocyte maturation in vitro involves activation of protein kinase B. Zhang L et al. Brain-derived neurotrophic factor (BDNF) can promote developmental competence in mammalian oocytes during in vitro maturation, but the signal transduction pathways are not clear. In this study, we investigated (using western blots) the effects of BDNF on the phosphorylation of protein kinase B (PKB) and mitogen-activated protein kinase (MAPK) in mouse oocytes and cumulus cells cultured in vitro. Treatment with BDNF enhanced phosphorylation of PKB in oocytes at 2h (P=0.0006) and 3h (P<0.0001) of in vitro maturation, compared with control oocytes. However, the pan-specific tyrosine kinase (Trk) inhibitor K252a together with BDNF completely inhibited phosphorylation of PKB in the oocytes. Furthermore, BDNF increased phosphorylation of MAPK in oocytes at 16h of in vitro maturation (P=0.0041), but K252a together with BDNF did not reduce phosphorylation of MAPK in the oocytes. For cumulus cells, BDNF significantly prolonged the phosphorylation of PKB and MAPK and increased the total amounts of PKB and MAPK proteins after 16h of in vitro maturation. However, BDNF did not affect apoptosis of the cumulus cells during oocyte maturation in vitro. In conclusion, the PKB pathway is likely to be one signaling cascade activated by BDNF in combination with the TrkB receptor, whereas the MAPK pathway is not involved. These findings may have relevance for BDNF-induced promotion of developmental capacity of in vitro-matured oocytes. Parthenogenic blastocysts derived from cumulus-free in vitro matured human oocytes. McElroy SL et al. BACKGROUND: Approximately 20% of oocytes are classified as immature and discarded following intracytoplasmic sperm injection (ICSI) procedures. These oocytes are obtained from gonadotropin-stimulated patients, and are routinely removed from the cumulus cells which normally would mature the oocytes. Given the ready access to these human oocytes, they represent a potential resource for both clinical and basic science application. However culture conditions for the maturation of cumulus-free oocytes have not been optimized. We aimed to improve maturation conditions for cumulus-free oocytes via culture with ovarian paracrine/autocrine factors identified by single cell analysis. METHODOLOGY/PRINCIPAL FINDING: Immature human oocytes were matured in vitro via supplementation with ovarian paracrine/autocrine factors that were selected based on expression of ligands in the cumulus cells and their corresponding receptors in oocytes. Matured oocytes were artificially activated to assess developmental competence. Gene expression profiles of parthenotes were compared to IVF/ICSI embryos at morula and blastocyst stages. Following incubation in medium supplemented with ovarian factors (BDNF, IGF-I, estradiol, GDNF, FGF2 and leptin), a greater percentage of oocytes demonstrated nuclear maturation and subsequently, underwent parthenogenesis relative to control. Similarly, cytoplasmic maturation was also improved as indicated by development to blastocyst stage. Parthenogenic blastocysts exhibited mRNA expression profiles similar to those of blastocysts obtained after IVF/ICSI with the exception for MKLP2 and PEG1. CONCLUSIONS/SIGNIFICANCE: Human cumulus-free oocytes from hormone-stimulated cycles are capable of developing to blastocysts when cultured with ovarian factor supplementation. Our improved IVM culture conditions may be used for obtaining mature oocytes for clinical purposes and/or for derivation of embryonic stem cells following parthenogenesis or nuclear transfer. The role of brain-derived neurotrophic factor in mouse oocyte maturation in vitro. Zhang L et al. Brain-derived neurotrophic factor (BDNF) can promote developmental competence in mammalian oocytes during in vitro maturation (IVM), but the role of BDNF in oocyte maturation at cellular level is not still clear. In this study, mouse cumulus-enclosed oocytes subjected to IVM were fertilized and cultured to blastocyst stage. Meiotic spindle configuration and cortical granules distribution during oocyte maturation in vitro were assessed by using immunofluorescence and laser confocal microscopy. The results showed that BDNF contributed to the complete preimplantation development of mouse oocytes compared to the control oocytes (13.78% vs. 5.92%; P<0.05). Further, BDNF did not accelerate nuclear maturation of IVM oocytes. For the BDNF-treated oocytes at meiosis I, Meiotic spindle areas were significantly smaller and the number of cytoplasmic microtubule organizing centers was greater than that in the control, and the percentages of oocytes showed spindles positioned near the oolemma and a well-formed cortical granule-free domain were significantly higher than that of the control. These morphological characteristics of the BDNF-treated oocytes were much closer to the oocytes matured in vivo than those of the control oocytes. In conclusion, BDNF can promote the developmental competence of mouse IVM oocytes, by improving the meiotic spindle configuration and location and cortical granules distribution at meiosis. Gonadotrophin-induced paracrine regulation of human oocyte maturation by BDNF and GDNF secreted by granulosa cells. Zhao P et al. BACKGROUND In mammalian ovaries, diverse paracrine factors have been identified to mediate or modulate LH-induced changes during ovulation. Due to the difficulty in obtaining non-stimulated granulosa cells during IVF, little is known about the LH-induced paracrine factors in the human ovary. Based on earlier studies using murine ovarian cells showing the paracrine roles of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) in promoting oocyte maturation, we investigated the expression of these ligands in human granulosa cells and their regulation of human oocyte development. METHODS Non-stimulated granulosa cells were obtained from non-stimulated IVM (in vitro maturation) patients after oocyte retrieval. Women undergoing non-stimulated IVM treatment at a mean age of 30.8 ? 1.3 (n = 10) were recruited for this study. Immature oocytes and granulosa cells were collected from IVF patients undergoing gonadotrophin stimulation and ICSI. Immunocytochemical analyses of granulosa cells were carried out to investigate expression profiles of BDNF and GDNF, together with real-time RT-PCR to analyze the gonadotrophin regulation of BDNF and GDNF transcript levels. In addition, immature oocytes were cultured to analyze the regulation of oocyte maturation by BDNF and GDNF. RESULTS BDNF and GDNF were found to be expressed in non-stimulated granulosa cells. After gonadotrophin (FSH and/or hCG) treatment, transcripts levels for BDNF and GDNF were significantly increased (P < 0.05). In cultured immature oocytes, treatment with BDNF or GDNF promoted total yields of metaphase II oocytes. CONCLUSIONS These findings demonstrate that FSH and hCG treatments augment the expression of BDNF and GDNF by granulosa cells and that these granulosa-cell-derived factors are candidate paracrine factors capable of promoting oocyte maturation. | ||||
| Expression regulated by | LH, Growth Factors/ cytokines, mir10b | ||||
| Comment | BMP2 increases the production of BDNF through the upregulation of proBDNF and furin expression in human granulosa-lutein cells. Bai L et al. (2020) Locally produced in human granulosa cells of the developing follicle, bone morphogenetic protein 2 (BMP2) plays a crucial role in the regulation of ovarian folliculogenesis and luteal formation. Brain-derived neurotrophic factor (BDNF) is an intraovarian neurotrophic factor that has been shown to promote oocyte maturation and subsequent fertilization competency. At present, little is known regarding the intracellular regulation, assembly and secretion of endogenous BDNF in human granulosa cells. The aim of this study was to explore the effect of BMP2 on the expression and production of BDNF in human granulosa cells and the molecular mechanisms underlying this effect. An immortalized human granulosa cell line (SVOG) and primary human granulosa-lutein (hGL) cells were utilized as in vitro study models. Our results showed that BMP2 significantly increased the mRNA and secreted levels of BDNF. Additionally, BMP2 upregulated the expression of furin at the transcriptional and translational levels. Knockdown of endogenous furin partially attenuated the BMP2-induced increase in BDNF production, indicating that furin is involved in the maturation process of BDNF. Using pharmacological (kinase receptor inhibitors) and siRNA-mediated inhibition approaches, we demonstrated that BMP2-induced upregulation of BDNF and furin expression is most likely mediated by the activin receptor-like kinase (ALK)2/ALK3-SMAD4 signaling pathway. Notably, analysis using clinical samples revealed that there was a positive correlation between follicular fluid concentrations of BMP2 and those of BDNF. These results indicate that BMP2 increases the production of mature BDNF by upregulating the precursor BDNF and promoting the proteolytic processing of mature BDNF. Finally, we also investigated the effects of BMP2 on ovarian steroidogenesis and the results showed that BMP2 treatment significantly increased the accumulated level of estradiol (by upregulating the expression of FSH receptor and cytochrome P450 aromatase), whereas it decreased the accumulated level of progesterone (by downregulating the expression of LH receptors and steroidogenic acute regulatory protein) in primary hGL cells. Our findings provide a novel paracrine mechanism underlying the regulation of an intraovarian growth factor in human granulosa cells.////////////////// BDNF-induced expansion of cumulus-oocyte complexes in pigs was mediated by microRNA-205. Li C et al. (2016) The neurotrophin family of proteins is required for the survival and differentiation of the nervous system and is important to the development of reproductive tissues. The objectives of the present study were to detect the presence of the brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor protein in cumulus-oocyte complexes in pigs and to explore the role of microRNAs in the BDNF-induced in vitro maturation of oocytes. We demonstrate that both BDNF and tyrosine kinase receptor protein are expressed in porcine cumulus oocyte complexes. BDNF supplementation promotes the in vitro maturation of porcine oocytes. MiRNA-205 is downregulated during the BDNF-induced maturation of oocytes. The overexpression of miRNA-205 in granulosa cells and reporter gene assay shows that the marker gene ptx3 for cumulus expansion is the putative target gene of miR-205. Our data provide evidence that the BDNF-induced maturation of oocytes in pigs may be mediated by miR-205 through the regulation of potential target gene, ptx3.////////////////// MicroRNA-10b suppresses goat granulosa cell proliferation by targeting brain-derived neurotropic factor. Peng JY et al. (2015) Brain-derived neurotropic factor (BDNF) and its high-affinity receptor, tyrosine kinase receptor B, have been assumed to be involved in female reproduction and have recently shown to play an essential role in follicle activation and oocyte maturation. In this study, we analyzed the expression of miR-10b and BDNF in the ovary and discovered that the expression of miR-10b was higher in monotocous goat ovaries than in polytocous goat ovaries, whereas the expression pattern of BDNF in ovary was opposite. Moreover, human chorionic gonadotropin induced rapid and transient expression of BDNF messenger RNA and protein. In contrast, human chorionic gonadotropin upregulated miR-10b expression in a time-dependent manner. The BDNF gene was identified as a direct target of miR-10b using a dual-luciferase reporter assay. Transfection of granulosa cells with miR-10b decreased BDNF messenger RNA and protein levels. MiR-10b overexpression inhibited cell proliferation, whereas BDNF promoted cell proliferation. However, a combined treatment with miR-10b and BDNF promoted cell proliferation, indicating that the reintroduction of BDNF reversed the suppressive effect of miR-10b. These results demonstrate that miR-10b downregulates BDNF expression in granulosa cells by directly targeting the 3' untranslated regions and plays an important role in inhibiting granulosa cell proliferation by targeting BDNF.////////////////// | ||||
| Ovarian localization | Primordial Germ Cell, Oocyte, Cumulus, Granulosa, Follicular Fluid | ||||
| Comment | Chronic unpredictable stress decreases expression of brain-derived neurotrophic factor (BDNF) in mouse ovaries: relationship to oocytes developmental potential. Wu LM et al. Brain-derived neurotropic factor (BDNF) was originally described in the nervous system but has been shown to be expressed in ovary tissues recently, acting as a paracrine/autocrine regulator required for developments of follicles and oocytes. Although it is generally accepted that chronic stress impairs female reproduction and decreases the expression of BDNF in limbic structures of central nervous system, which contributes to mood disorder. However, it is not known whether chronic stress affects oocytes developments, nor whether it affects expression of BDNF in ovary. Differential expression and regulation by activin of the neurotrophins BDNF and NT4 during human and mouse ovarian development. Childs AJ et al. The tropomyosin-related kinase (Trk) B neurotrophin receptor is essential for ovarian germ cell survival and primordial follicle formation, but the contributions of its ligands, brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT4), are unknown. We have investigated their expression and regulation in developing human and mouse ovaries. BDNF expression increased with increasing gestation, expression of human NTF4 and of both Ntf5 and Bdnf in the mouse was unchanged. Bdnf expression was dramatically lower than Ntf5 in the mouse, but levels were comparable in the human. Human fetal ovarian somatic cells expressed BDNF. Activin A selectively regulated BDNF and Ntf5 expression in human and mouse, respectively, identifying an oocyte/somatic signaling pathway which might mediate the pro-survival effects of activin. These data reveal that expression and regulation of the TrkB ligands are differentially controlled in the developing ovaries of humans and mice, and identify BDNF as a potential regulator of germ cell fate in the human fetal ovary. Developmental Dynamics, 2010. (c) 2010 Wiley-Liss, Inc. Seifer DB, 2002 et al examined the human ovarian follicle for its possible secretion of BDNF and further studied mouse oocytes to determine BDNF's possible influence upon oocyte maturation. In a series of experiments derived from human specimens from in vitro fertilization following oocyte retrieval, BDNF was detected in human follicular fluid. To define the source of BDNF, cumulus granulosa cells were grown in cell culture for 1-2 d. BDNF protein increased over 24 h in the culture medium. Moreover, the release of BDNF was enhanced upon stimulation with cAMP or forskolin, an activator of cAMP. In contrast, mural granulosa (cells lining the follicle), oocytes, and embryos did not release appreciable quantities of BDNF. To examine possible targets of BDNF, mouse studies were used to localize the BDNF receptor, Trk B, immunocytochemically. The receptor was present on the surface of isolated oocytes. Moreover, BDNF promoted mouse oocyte maturation in culture. These experiments demonstrate for the first time the presence and secretion of BDNF from follicular cells in the human ovary and suggest a possible role for BDNF in the regulation and modulation of oocyte maturation. Polycystic ovary syndrome: brain-derived neurotrophic factor (BDNF) plasma and follicular fluid levels. Russo N et al. Polycystic ovary syndrome is one of the most common endocrine disorders in women of reproductive age. Features of PCOS are hyperandrogenism, chronic anovulation and polycystic ovaries on ultrasonography. Follicle development is a complex and carefully orchestrated phenomenon, involving gonadotropins and a rapidly expanding list of other intraovarian regulators, such as brain-derived neurotrophic factor (BDNF). The aim of this study is to evaluate BDNF in plasma and in follicular fluid in women affected by PCOS and in normal menstruating women. In PCOS patients the BDNF levels in plasma and in follicular fluid are higher than values obtained in healthy controls. Therefore we can hypothsize that high levels of luteinizing hormone, probably increase the secretion of BDNF in PCOS patients. | ||||
| Follicle stages | Primordial, Primary, Antral, Preovulatory, Corpus luteum, Follicular fluid | ||||
| Comment | BDNF Val66Met polymorphism is associated with Stage III-IV endometriosis and poor in vitro fertilization outcome. Zhang QY et al. BACKGROUNDThe recently identified human brain-derived neurotrophic factor (BDNF) Val66Met polymorphism was found to be associated with altered susceptibility to some neuropsychiatric disorders. Interestingly, BDNF together with its receptors TrkB and p75 are extensively expressed in female reproduction system. The aim of this study is to investigate whether the BDNF Val66Met polymorphism plays a role in endometriosis, endometriosis-related infertility and the outcomes of IVF and embryo transfer (IVF-ET).METHODSA case-control study included 425 endometriosis patients and 244 control Chinese Han women. The genotyping of the BDNF Val66Met polymorphism was performed by the fluorescence resonance energy transfer method. The plasma and follicular fluid concentrations of BDNF on the day of oocyte retrieval were measured by ELISA. The general clinical data from the endometriosis-related and tubal obstructed infertile patients treated with IVF-ET were analyzed.RESULTSThere was no association between the BDNF Val66Met polymorphism and overall endometriosis (P> 0.05), whereas higher genotype and allele frequencies of the BDNF(Met) polymorphism were found in the Stage III-IV endometriosis (both P< 0.01) and endometriosis-related infertile patients (both P< 0.05). Moreover, during IVF and embryo transfer (IVF-ET) treatment, fewer mature oocytes (P< 0.05) and lower fertilization rate (P< 0.01) were found in BDNF(Met/Met) carriers compared with those in BDNF(Val/Val) carriers with infertility. Follicular-fluid BDNF concentration in BDNF(Met/Met) carriers was lower compared with that in BDNF(Val/Val) individuals (P< 0.01).CONCLUSIONSOur results suggest that the BDNF(Met) single-nucleotide polymorphism might contribute to the increased susceptibility to the Stage III-IV endometriosis and endometriosis-related infertility. Moreover, infertile patients with the BDNF(Met/Met) genotype had a poorer IVF outcome compared with the BDNF(Val/Val) genotype individuals, which might in part be due to the decreased BDNF levels in follicular fluids after controlled ovarian hyperstimulation. Brain derived neurotrophic factor circulating levels in patients undergoing IVF. Monteleone P et al. PURPOSE: The aim of the study was to measure circulating BDNF levels, a neurotrophin recently identified in the ovary, in parallel with estradiol, to verify if assessing this factor could add any predictive value to the outcome of in vitro fertilization. METHODS: Blood sampling for BDNF and estradiol was performed in 23 subjects undergoing IVF on day 1 (D1), day 8 (D8), day of HCG administration (DHCG) and day of oocyte retrieval.(DOR). RESULTS: There was a positive correlation between BDNF and estradiol throughout the stimulation cycle in all subjects. In both pregnant and nonpregnant patients, the values of BDNF grew significantly only between D8 and DHCG and remained constant until DOR. Between-group comparisons showed no statistically significant differences in both BDNF and estradiol values throughout the IVF cycle. CONCLUSION: Although BDNF plasma concentrations are not seemingly predictive of IVF outcome, this neurotrophin is highly correlated to estradiol levels and seems to be an important factor especially in the periovulatory period. Brain-derived neurotrophic factor expression in granulosa lutein cells. Dominguez MA et al. Brain-derived neurotrophic factor (BDNF) is thought to play a role in follicle activation and oocyte maturation. It is postulated that BDNF and its receptor, tyrosine kinase receptor B (TrkB), may also play a role in maintaining the corpus luteum. Therefore, human granulosa lutein cells (GLC) were obtained from women undergoing ovulation induction and treated with increasing concentrations of cAMP (0, 125, 500 and 1000?mol/l). BDNF and progesterone concentrations were quantified by enzyme-linked immunosorbent assay. cAMP treatment significantly increased progesterone output but had no effect on BDNF concentration in the spent media. However, the BDNF concentration was significantly increased in GLC lysates. To assess the expression of BDNF and TrkB in active versus regressing corpora lutea, ovaries from adult female BALBc mice (n=4) from each day of the oestrous cycle were processed for immunohistochemistry. Two markers of luteal activity were used (3?hydroxysteroid dehydrogenase and tenascin-X). There was a trend towards higher BDNF and TrkB H-scores in active versus regressing corpus lutea. In conclusion, intracellular BNDF concentrations were dose-dependently increased by cAMP but treatments had no effect on BDNF output. It is speculated that BDNF contributes in an autocrine manner to GLC survival in the active corpus luteum. Neurotrophins and their receptors play a central role in nerve cell proliferation, differentiation, and survival. Members of the neurotrophin family and their receptors have been shown to be expressed in extra-neuronal tissues including the reproductive tract. Evidence has been brought forward in the literature which suggests that brain-derived neurotrophic factor (BDNF) is an intra-ovarian cytokine thought to play a role in the development of primordial follicles, folliculogenesis and oocyte maturation. We now postulate that BDNF and its receptor, tyrosine kinase receptor B (TrkB), may also play a role in maintaining the corpus luteum. In this study, human granulosa lutein cells (GLC) were obtained from women undergoing ovulation induction for IVF. GLC were treated with increasing concentrations of cAMP (0, 125, 500 and 1000?mol/l). BDNF and progesterone concentrations were quantified by ELISA. cAMP treatment significantly increased progesterone output but had no effect on BDNF concentration in the spent culture media. However, the BDNF concentration was significantly increased in GLC lysates. To assess the expression of BDNF and TrkB in active versus regressing corpora lutea, ovaries from adult female BALBc mice were processed for immunohistochemistry. There was a trend towards higher mean BDNF and TrkB H-scores in active versus regressing CLs. We conclude that cAMP treatment dose-dependently increased intracellular BDNF concentrations but had no effect on BDNF output. Hence, we speculate that BDNF contributes in an autocrine manner to survival of GLC in active corpora lutea. | ||||
| Phenotypes |
PCO (polycystic ovarian syndrome) |
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| Mutations |
6 mutations
Species: mouse
Species: mouse
Species: human
Species: human
Species: human
Species: human
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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