| nerve growth factor | OKDB#: 1153 |
| Symbols: | NGF | Species: | human | ||
| Synonyms: | NGFB, HSAN5, Beta-NGF | Locus: | 1p13.2 in Homo sapiens |
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| General Comment |
Nerve growth factor (NGF) epitomizes a family of proteins known as the neurotrophins (NTs),
which are required for the survival and differentiation of neurons within both the central and
peripheral nervous system.
NGF consists of 3 types of subunits, alpha, beta and gamma, which
specifically interact to form a 7S, 130,000-molecular weight complex. This complex contains 2 identical 118-amino
acid beta-chains, which are solely responsible for nerve growth stimulating activity of NGF.
NCBI Summary: This gene is a member of the NGF-beta family and encodes a secreted protein which homodimerizes and is incorporated into a larger complex. This protein has nerve growth stimulating activity and the complex is involved in the regulation of growth and the differentiation of sympathetic and certain sensory neurons. Mutations in this gene have been associated with hereditary sensory and autonomic neuropathy, type 5 (HSAN5), and dysregulation of this gene's expression is associated with allergic rhinitis. [provided by RefSeq, Jul 2008] |
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| General function | Ligand, Growth factor | ||||
| Comment | |||||
| Cellular localization | Secreted | ||||
| Comment | Excessive ovarian production of nerve growth factor facilitates development of cystic ovarian morphology in mice and is a feature of polycystic ovarian syndrome in humans. Dissen GA et al. (2009) Although ovarian nerve growth factor (NGF) facilitates follicular development and ovulation, an excess of the neurotrophin in the rodent ovary reduces ovulatory capacity and causes development of precystic follicles. Here we show that ovarian NGF production is enhanced in patients with polycystic ovarian syndrome (PCOS) and that transgenically driven overproduction of NGF targeted to the ovary results in cystic morphology, when accompanied by elevated LH levels. NGF levels are increased in the follicular fluid from PCOS ovaries and in the culture medium of granulosa cells from PCOS patients, as compared with non-PCOS patients. Ovaries from transgenic mice carrying the NGF gene targeted to thecal-interstitial cells by the 17alpha-hydroxylase gene promoter produce more NGF than wild-type (WT) ovaries and are hyperinnervated by sympathetic nerves. Antral follicle growth is arrested resulting in accumulation of intermediate size follicles, many of which are apoptotic. Peripubertal transgenic mice respond to a gonadotropin challenge with a greater increase in plasma 17-hydroxyprogesterone, estradiol, and testosterone levels than WT controls. Transgenic mice also exhibit a reduced ovulatory response, delayed puberty, and reduced fertility, as assessed by a prolonged interval between litters, and a reduced number of pups per litter. Sustained, but mild, elevation of plasma LH levels results in a heightened incidence of ovarian follicular cysts in transgenic mice as compared with WT controls. These results suggest that overproduction of ovarian NGF is a component of polycystic ovarian morphology in both humans and rodents and that a persistent elevation in plasma LH levels is required for the morphological abnormalities to appear.////////////////// | ||||
| Ovarian function | Follicle development, Initiation of primordial follicle growth, Preantral follicle growth, Antral follicle growth, Cumulus expansion, Ovulation, Steroid metabolism, Germ cell development, Oocyte maturation | ||||
| Comment | Restricting the induction of NGF in ovarian stroma engenders selective follicular activation through the mTOR signaling pathway. He Y et al. (2017) In mammalian ovaries, primordial follicles remain in a quiescent state until activation by the surrounding microenvironment. Ovarian intervention, for example, ovarian cystectomy, ovarian wedge resection or laser drilling therapies for polycystic ovarian syndrome, has long been reported to change follicular development by an unknown mechanism(s). Herein, we established a murine model with partial ovarian resection of one ovary unilaterally, with the contralateral ovary undamaged. We found the injury accelerated follicular activation and development through the mTORC1 signaling pathway. Moreover, the stimulation of primordial follicles was restricted near the incision site where the mTORC1 pathway showed sequential activation beginning at the interstitial cells and proceeding to the primordial follicles. Total and polysome-associated RNA-seq revealed the increase of the nerve growth factor (NGF) family member, in both two fractions and immunostaining showed the restricted induction of NGF near the incision site. In cultured newborn ovaries, NGF demonstrated increase of follicular activation, and moreover, the NGF inhibitor K252a effectively blocked activation of primordial follicles stimulated by the surgery. We liken ovulation in mammals to minor tissue trauma, which happens naturally and cyclically in the body. As the increase in NGF accompanied the accumulation of activated primordial follicles after ovulation, our study may represent a common mechanism for selective follicular activation induced by a localized increase in NGF in interstitial cells and mediated via the mTOR signaling pathway. In addition, the NGF inhibitor K252a and the mTOR inhibitor rapamycin constitute good candidates for protecting follicular reserve against over exhaustion after ovarian surgery.////////////////// RAPID COMMUNICATION: Nerve growth factor influences cleavage rate and embryo development in sheep. Crispo M et al. (2016) Recent information about Nerve growth factor (NGF), a protein traditionally associated to the nervous system that regulates survival and maturation of developing neurons, suggests that it may exert action also on different levels in the reproductive system. The aim of this study was to evaluate the effect of NGF added during in vitro oocyte maturation, fertilization or in vitro embryo development in sheep. Nerve growth factor was supplemented to the culture medium at 0, 100, or 1,000 ng/mL, during either in vitro maturation (Exp. 1), in vitro fertilization (Exp. 2), or in vitro culture (Exp. 3). In addition, NGF mRNA expression was determined in cumulus cells and oocytes. Nerve growth factor induced early cleavage when added during oocyte maturation or fertilization, improved embryo development when added during fertilization, and had no significant effect when added during embryo culture. In general, the effect was more evident with 100 rather than 1,000 ng/mL (P < 0.05). Expression of endogenous NGF was not detected in oocytes, and increased in cumulus cells when 1,000 ng/mL of NGF was added during fertilization, but not during maturation and embryo culture. In conclusion, the addition of NGF during oocyte maturation and fertilization affects in vitro cleavage and embryo development in sheep. We suggest a possible effect of this growth factor on oocyte maturation and mainly on the fertilization process.////////////////// Pro-nerve growth factor in the ovary and human granulosa cells. Meinel S et al. (2015) Pro-nerve growth factor must be cleaved to generate mature NGF, which was suggested to be a factor involved in ovarian physiology and pathology. Extracellular proNGF can induce cell death in many tissues. Whether extracellular proNGF exists in the ovary and may play a role in the death of follicular cells or atresia was unknown. Immunohistochemistry of human and rhesus monkey ovarian sections was performed. IVF-derived follicular fluid and human granulosa cells were studied by RT-PCR, qPCR, Western blotting, ATP- and caspase-assays. Immunohistochemistry of ovarian sections identified proNGF in granulosa cells and Western blotting of human isolated granulosa cells confirmed the presence of proNGF. Ovarian granulosa cells thus produce proNGF. Recombinant human proNGF even at high concentrations did not affect the levels of ATP or the activity of caspase 3/7, indicating that in granulosa cells proNGF does not induce death. In contrast, mature NGF, which was detected previously in follicular fluid, may be a trophic molecule for granulosa cells with unexpected functions. We found that in contrast to proNGF, NGF increased the levels of the transcription factor early growth response 1 and of the enzyme choline acetyl-transferase. A mechanism for the generation of mature NGF from proNGF in the follicular fluid may be extracellular enzymatic cleavage. The enzyme MMP7 is known to cleave proNGF and was identified in follicular fluid and as a product of granulosa cells. Thus the generation of NGF in the ovarian follicle may depend on MMP7.////////////////// NGF promotes mouse granulosa cell proliferation by inhibiting ESR2 mediated down-regulation of CDKN1A. Wang Y et al. (2015) Nerve growth factor (NGF) is known to play key roles in ovarian follicular development, such as the assembly of early follicles and follicular ovulation through its high-affinity receptor, tyrosine kinase receptor A (trkA). Herein, the molecular mechanism controlling NGF-induced granulosa cell (GC) proliferation was not clear. In this study, we found that NGF is abundant in preantral GCs and knockdown of trkA in GCs attenuated NGF-induced GC proliferation and further decreased the levels of phosphorylated extracellular regulated protein kinases 1/2 (ERK1/2). Cyclin-dependent kinase inhibitor 1A (CDKN1A), also named p21, a factor which could be either a negative or a positive regulator via transformation related protein 53 (TRP53, also named p53)-dependent or independent pathways in cell proliferation, was up-regulated during the process of NGF-induced GC proliferation. Blockade of trkA (K252α) and ERK1/2 (U0126) in GCs decreased NGF-induced expression of CDKN1A and did not alter the expression of TRP53, indicating that NGF stimulates CDKN1A expression via the trkA-ERK1/2 pathway in a TRP53-independent manner. Meanwhile, ESR2, a tumor suppressor which is exclusively expressed in GCs, was suppressed in NGF-induced GC proliferation, and this effect was abrogated by U0126. Blockade of ESR2 (ICI182,780) caused the promotion of GC proliferation and CDKN1A expression, indicating that ESR2 may be downstream of the ERK1/2 pathway in mediating the effect of CDKN1A on NGF-induced GC proliferation. Therefore, ESR2 may be involved in the integration of intracellular signal cascades and cell cycle proteins in affecting GC proliferation. Here, we provide mechanistic insights into the roles of CDKN1A in NGF-induced GC proliferation. Understanding potential cross-points between CDKN1A and ESR2 affecting GC proliferation will help in the discovery of new therapeutic targets in some female infertility disorders.////////////////// Ovulation-inducing factor (OIF/NGF) from seminal plasma origin enhances Corpus Luteum function in llamas regardless the preovulatory follicle diameter. Silva M 2014 et al. Ovulation-inducing factor (OIF) is a protein present in llama seminal plasma that has recently been identified as ?Nerve Growth Factor (NGF) and it induces not only a high rate of ovulation but also appears to have luteotrophic properties in this species. A 2-by-2 experimental design was used to determine the effect of treatments (OIF/NGF vs GnRH) and categories of preovulatory follicle diameter (7-10 vs >10mm) on ovulation rate, CL diameter and function in llamas. Llamas (n=32 llamas per group) were randomly assigned to receive an intramuscular dose of: (a) 1mg purified OIF/NGF in the presence of a follicle of 7-10mm in diameter; (b) 50?g of GnRH in the presence of a follicle of 7-10mm in diameter; (c) 1mg purified OIF/NGF in the presence of a follicle >10mm in diameter; (d) 50?g of GnRH in the presence of a follicle >10mm in diameter. Llamas were examined by ultrasonography every 12h from treatment to Day 2 (Day 0=treatment) to detect ovulation, and again on Day 8 to determine CL diameter. Ovulation rates did not differ among groups. There was an effect of preovulatory follicle size on Corpus Luteum diameter at Day 8 (P<0.001), however plasma progesterone concentration (n=15/per group) was higher (P<0.05) in the OIF/NGF - than that of the GnRH - treated group by the same day. We conclude that OIF/NGF treatment enhances CL function regardless preovulatory follicle size at the time of treatment. ///////////////////////// Nerve Growth Factor Promotes the Survival of Goat Preantral Follicles Cultured in vitro. Chaves RN et al. The aim of this study was to investigate the effects of nerve growth factor (NGF) on the in vitro culture of goat preantral follicles. Ovarian cortex fragments were cultured in alpha-MEM+ supplemented with 0, 1, 10, 50, 100 or 200 ng/ml NGF for 1 or 7 days. Small fragments of noncultured ovarian tissue as well as those cultured for 1 or 7 days were processed for histology and transmission electron microscopy. The results showed that after 1 or 7 days of culture at all concentrations of NGF, except at 1 ng/ml after 1 day of culture, there was a significant reduction in the percentage of normal follicles compared to noncultured tissues. At higher NGF concentrations (100 and 200 ng/ml) after 7 days of culture, there was a significant reduction in the percentage of normal follicles compared to tissues cultured in alpha-MEM+ alone or at the other concentrations of NGF. It is important to note that ultrastructural and fluorescent analyses confirmed only the integrity of follicles cultured with 1 ng/ml of NGF after 7 days. In contrast to noncultured control tissues, the percentage of developing follicles was significantly increased at all concentrations of NGF after 1 or 7 days of culture. We observed that follicular diameter was greater at 1 and 10 ng/ml NGF after culture for 7 days than at the other concentrations but was similar to follicles cultured in alpha-MEM+ alone. In conclusion, NGF improved the survival of goat preantral follicles cultured in vitro in a dose-dependent manner. Dissen GA, et al 2000 reported direct effects of nerve growth factor on thecal cells from antral ovarian follicles. These results suggest that the contribution of NGF to the ovulatory process includes a stimulatory effect of the neurotrophin on steroidogenesis, PGE2 formation, and proliferative activity of thecal compartment cells. Nerve Growth Factor-Dependent Activation of trkA Receptors in the Human Ovary Results in Synthesis of FSH Receptors and Estrogen Secretion. Salas C et al. Context: Earlier studies showed that nerve growth factor (NGF) induces the expression of functional FSH receptors (FSHR) in preantral follicles of the developing rat ovary. Objective: We studied if NGF can affect granulosa cell (GC) function in human periovulatory follicles using intact human ovaries and isolated human GCs. Patients and Interventions: Human GCs were obtained from IVF patients and normal ovaries from women with elective pelvic surgery for non-ovarian indications. Results: In normal ovaries, NGF and trkA (NGF's high-affinity receptor), were detected by immunohistochemistry in GCs of preantral and antral follicles. NGF and trkA are also present in theca cells of antral follicles. Both freshly collected and cultured GCs contained immunoreactive NGF and trkA, in addition to their respective mRNAs. Human GCs respond to NGF with increased estradiol (E2) secretion and a reduction in progesterone (P) output. Exposure of human GCs to NGF increased FSHR mRNA content within 18 h of treatment, and this effect was blocked by trk tyrosine kinase blocker K-252a. Also, cells pre-exposed to NGF released significantly more E2 in response to hFSH than cells not pretreated with the neurotrophin, showing that NGF-induced increase in FSHR gene expression results in the formation of functional FSHRs. Conclusions: These results suggest that one of the functions of NGF in the preovulatory human ovary is to increase the secretion of E2, while preventing early luteinization via an inhibitory effect on P secretion. NGF stimulates E2 secretion both directly and by increasing the formation of FSH receptors. Effects of nerve growth factor (NGF) on blood vessels area and expression of the angiogenic factors VEGF and TGFbeta1 in the rat ovary. Julio-Pieper M et al. ABSTRACT: BACKGROUND: Angiogenesis is a crucial process in follicular development and luteogenesis. The nerve growth factor (NGF) promotes angiogenesis in various tissues. An impaired production of this neurotrophin has been associated with delayed wound healing. A variety of ovarian functions are regulated by NGF, but its effects on ovarian angiogenesis remain unknown. The aim of this study was to elucidate if NGF modulates 1) follicular vascularization and 2) ovarian expression of two angiogenic factors: vascular endothelial growth factor (VEGF) and transforming growth factor beta 1 (TGFbeta1), in the rat ovary. RESULTS: In cultured neonatal rat ovaries, NGF increased VEGF mRNA and protein levels, whereas TGFbeta1 expression did not change. Sectioning of the superior ovarian nerve, which increases ovarian NGF protein content, augmented VEGF immunoreactivity and the area of capillary vessels in ovaries of prepuberal rats compared to control ovaries. CONCLUSIONS: Results indicate that NGF may be important in the maintenance of the follicular and luteal vasculature in adult rodents, either indirectly, by increasing the expression of VEGF in the ovary, or directly via promoting the proliferation of vascular cells. This data suggests that a disruption on NGF regulation could be a component in ovarian disorders related with impaired angiogenesis. | ||||
| Expression regulated by | |||||
| Comment | Preovulatory rise of NGF in ovine follicular fluid: possible involvement in the control of oocyte maturation. Barboni B, et al . Since nerve growth factor (NGF) is produced in vitro by granulosa cells after gonadotropin stimulation, the present research has been designed to investigate whether this neurotropin is involved in the events triggered by the gonadotropin surge that lead the follicle to ovulate a mature oocyte. To this aim, NGF levels in follicular fluid, collected before or 20 hours after the gonadotropin surge, was measured by ELISA. To evaluate whether NGF may have a non-neurotropic effect on follicle cells, the presence of NGF receptors was investigated by immunohistochemistry and further evaluated by analysing the tyrosine-phosphorylation pattern after NGF stimulation in vitro. The effect of NGF on the degree of cumulus expansion, cumulus-oocyte metabolic coupling, and meiotic maturation was finally studied by using the culture of follicle-enclosed oocyte. The results demonstrate that GnRH causes a dramatic rise of NGF in large follicles. Immunohistochemistry revealed a discrete positivity for trkA receptors localised in cumulus cells. Tyrosine phosphorylation pattern confirms that somatic cells are capable to transduce NGF signal. By contrast, all the oocytes examined were negative for trkA and did not change the phosphorylation pattern after NGF. In vitro NGF (100 ng/ml) induced a marked cumulus expansion and a progressive cumulus-oocyte uncoupling similar to that produced by gonadotropins. The addition of NGF also caused the resumption of meiosis in more than 70% of the oocytes analysed with an effect that is only slightly less pronounced than that of gonadotropins (80%). The increase in NGF secretion following gonadotropin surge suggests that this neurotropin may be involved in the control of oocyte maturation. | ||||
| Ovarian localization | Oocyte, Granulosa, Theca | ||||
| Comment | Lara HE, et al reported that the gene encoding nerve growth factor is expressed in the immature rat ovary and the effect of denervation and hormonal treatment. The rat ovary is innervated by sympathetic nerve fibers. Blot hybridization of ovarian polyadenylated RNA (A+-RNA) to a NGF cRNA probe revealed the presence of a 1.3- to 1.4-kilobase (kb) mRNA species similar to mature NGF mRNA detected in mouse submaxillary gland, a source rich in NGF. Quantitation of NGF protein by a sensitive and specific two-site enzyme immunoassay demonstrated the presence of NGF in juvenile ovaries at levels comparable to those found in other sympathetically innervated tissues. Neither denervation of the ovary nor treatment with gonadotropins (hCG and FSH) or somatomammotropins (PRL and GH) affected the levels of NGF mRNA. However, denervation significantly increased NGF levels, suggesting that, as in other target tissues, denervation prevents the retrograde transport of NGF by the sympathetic terminals and leads to accumulation of the protein at its site of production. It is concluded that 1) the developing ovary is able to both transcribe the NGF gene and translate its mRNA into NGF protein; and 2) the NGF content in the ovary is regulated by its innervation. The results provide the biochemical basis for the concept, elaborated in the companion paper, that NGF through its trophic actions on ovarian sympathetic neurons contributes to the regulation of ovarian development and, hence, to the acquisition of female reproductive capacity. Dissen GA, et al reported the expression of neurotrophins and their receptors in the mammalian ovary is developmentally regulated with changes at the time of folliculogenesis. The NGF and trkA genes showed a different pattern of expression, as the ovarian content of both NGF and trkA mRNA decreased at the time of folliculogenesis.///////Nerve growth factor (NGF) levels in follicular fluid of infertile patients undergoing to in vitro fertilization (IVF) cycle. Palumbo MA 2013 et al. Abstract Objective: The aim of this study was to determine the levels of NGF in follicular fluid and serum samples, and to correlate them with some characteristics of the patients (age) and of the IVF protocol (E2 levels, number of collected oocytes, used FSHr IU) to investigate its rule in the folliculogenesis. Methods: This study examined a sample of 78 women undergoing to FIVET/ICSI cycles since October 2011 to March 2013. NGF levels were determinated in follicular fluid (FF) and serum sample using enzyme immunoassay ELISA kit for NGF. Results: The NGF level was significantly higher in FF (213.76?pg/ml) than in basal serum (46.47?pg/ml (p? | ||||
| Follicle stages | Primary, Secondary, Antral, Preovulatory | ||||
| Comment | Expression of Nerve Growth Factor (NGF), and Its Receptors trkA and p75 in Ovaries of the Cyclic Golden Hamster (Mesocricetus auratus) and the Regulation of Their Production by Luteinizing Hormone Shi Z, et al . In the present study, changes in localization of nerve growth factor (NGF) and its receptors, trkA and p75 in the ovary were investigated during the estrous cycle of the golden hamster. The effect of LH surge on changes in localization of NGF, trkA and p75 in the ovary was also investigated. NGF and its receptors trkA and p75 were localized in oocytes, granulosa cells and theca cells of various stages of follicles throughout the estrous cycle. NGF and its two receptors were also present in numerous interstitial cells and luteal cells. The number of interstitial cells staining positively for NGF and its two receptors was greater in ovaries of day 1 (day 1=day of ovulation) than the other days during the estrous cycle. Treatment with the antiserum against luteinizing hormone releasing hormone (LHRH-AS) at 1100 h on day 4 completely blocked ovulation. There were few positive reactions for NGF and its two receptors in interstitial cells 24 hr after LHRH-AS injection. The effect of LHRH-AS treatment was blocked by a single injection of 10 IU human chorionic gonadotropin. The distinct widespread distribution of NGF and its two receptors in the ovary of golden hamsters suggest that NGF may be an important growth factor for regulation of ovarian function. Furthermore, the LH surge may be an important factor for inducing production of NGF and its two receptors in interstitial cells of the cyclic golden hamster. Presence of NGF and its receptors in ovaries from human fetuses and adults. Abir R, et al . The ability to mature human primordial follicles in vitro would assist fertility restoration. However, the signals initiating growth of primordial follicles are unknown. Growth factors such as nerve growth factor (NGF) may play a role in this process. To investigate the expression of NGF and its receptors, p75 and TrkA, in early developing follicles (mostly primordial, primary and secondary follicles), ten ovarian samples from adolescents/adults aged 13-39 and 33 ovaries from human fetuses aged 19-33 gestational weeks (GW) were obtained and immediately fixed or frozen. The fixed samples were prepared for a study of immunocytochemical staining of NGF and its two receptors. Total RNA was extracted from the frozen ovarian samples, and the expression of NGF, TrkA and p75 was investigated by RT-PCR. Products were resolved by 1% agarose gel electrophoresis and image analysis. Immunocytochemical staining revealed the expression of NGF in granulosa cells (GC) and oocytes; TrkA was mainly in oocytes and in GC in minority of the samples; and p75 was in some of the stroma cells from fetuses aged less than 22 GW. Transcripts of NGF and TrkA were identified by RT-PCR in all samples, while those for p75 were detected only in ovarian samples from fetuses aged less than 22 GW. To elucidate if NGF is indeed involved in growth initiation of human primordial follicles, it should be added to their culture medium. The immunocytochemical detection of p75 in some of the stroma cells and transcripts in ovarian samples of fetuses less than 22 GW may suggest its role in follicular assembly. | ||||
| Phenotypes |
PCO (polycystic ovarian syndrome) |
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| Mutations |
5 mutations
Species: mouse
Species: mouse
Species: mouse
Species: mouse
Species: mouse
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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| created: | April 25, 2001, 1:38 p.m. | by: |
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| last update: | Sept. 9, 2020, 10:02 a.m. | by: | hsueh email: |
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