Nerve growth factor receptor (NGFR; 162010) is also referred to as p75(NTR) due
to its molecular mass and its ability to bind at low affinity not only NGF (see 162030), but also other neurotrophins,
including brain-derived neurotrophic factor (BDNF; 113505), neurotrophin-3 (NTF3; 162660), and neurotrophin-4/5
(NTF5; 162662). As a monomer, NGFR binds NGF with low affinity. Higher affinity binding is achieved by
association with higher molecular mass, low-affinity neurotrophin receptors, namely the tropomyosin receptor kinases,
TRKA (NTRK1), TRKB (NTRK2; OMIM 600456), and TRKC (NTRK3; OMIM 191316). TRKA, TRKB, and TRKC are specific for
or 'preferred by' NGF, NTF5 and BDNF, and NTF3, respectively .
General function
Receptor, Enzyme, Transferase
Comment
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.
Knockdown of TrkA in cumulus oocyte complexes (COCs) inhibits EGF-induced cumulus expansion by down-regulation of IL-6. Wang Y 2013 et al.
Tyrosine kinase receptor A (TrkA), the high-affinity receptor of nerve growth factor (NGF), is known to play key roles in ovarian follicular development, such as assembly of early follicles and follicular ovulation. However, little is known about the roles of TrkA in cumulus oocyte complex (COC) expansion. In this study, we found that TrkA was abundant in large antral follicles and knockdown of TrkA in COCs attenuated epidermal growth factor (EGF)-induced COC expansion and further decreased the ovulation rate. The effect of TrkA on COC expansion was not mediated through downstream EGF effectors, phosphorylation of extracellular regulated protein kinases 1/2 (ERK1/2) or drosophila mothers against decapentaplegic protein (SMAD), or through up-regulation of COC expansion-related transcripts such as prostaglandin-endoperoxide synthase 2 (Ptgs2), hyaluronan synthase 2 (Has2), TNF-induced protein 6 (Tnfaip6) or pentraxin 3 (Ptx3). However, pharmacological blockade of TrkA transducing activity (K252a) in COCs decreased the mRNA expression and protein secretion of interleukin-6 (IL-6), identified from mRNA microarray of K252a-treated COCs. Meanwhile, knockdown of IL-6 attenuated EGF-induced COC expansion. In addition, IL-6 rescued the inhibitory effect of K252a on EGF-induced cumulus expansion. Therefore, IL-6 may act as a new potential cumulus expansion-related transcript, which may be involved in the integration of TrkA and EGF signaling in affecting COC expansion. Here, we provide mechanistic insights into the roles of TrkA in EGF-induced cumulus expansion. Understanding potential cross-points between TrkA and EGF affecting cumulus expansion will help in the discovery of new therapeutic targets in ovulation-related diseases.
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Dissen GA, et al 1996 reproted a role for trkA nerve growth factor receptors in mammalian
ovulation.
They reported that trkA, the NGF receptor tyrosine
kinase, is involved in the acute activational process that leads to the first
ovulation. The trkA gene becomes transiently expressed in periovulatory
follicules at the time of the first preovulatory surge of gonadotropins at puberty;
the increase in trkA messenger RNA (mRNA) content is dramatic ( > 100-fold),
but transient (approximately 9 h). No such changes in trkB or trkC mRNA were
observed; the abundance of these mRNAs, which encode the receptor tyrosine
kinase for NT-4/5 and brain-derived neurotrophic factor, and NT-3, respectively,
remained at very low levels throughout puberty. In vivo and in vitro experiments
demonstrated that the activation of trkA gene expression is brought about by the
proestrous discharge of LH. The increase in trkA mRNA levels is mainly
localised to cells of the follicular wall and interstitial tissue of the ovary. NGF
mRNA abundance also increases at proestrus, with peak values detected about 5 h
before ovulation; as in the case of trkA mRNA, NGF mRNA was found in
thecal-interstitial cells. Both trkA and NGF protein, detected by
immunohistochemistry, were localized to this same ovarian compartment.
Interleukin-1 beta (IL-1 beta), a putative mediator of LH action, enhances both
trkA and NGF gene expression in ovarian cells, an effect prevented by IL-1ra, a
natural IL-1 beta receptor antagonist. Il-1 beta also stimulates PGE2 release, and
this effect was inhibited by both NGF antibodies and a trk receptor blocker, NGF
antibodies administered in vivo attenuated the increase in ovarian PGE2 synthesis
that antedates ovulation. Immunoneutralization of NGF action or pharmacological
blockade of trk tyrosine kinase activity targeted to one ovary resulted in the
ipsilateral inhibition of ovulation. The remarkably narrow time frame of trkA gene
activation at the completion of follicular growth suggests that NGF acting as a
neuroendocrinotrophic factor in a developmentally restricted manner contributes
to the acute cytodifferentiation process that leads to the first ovulation in
mammals.
Gene whose expression is detected by cDNA array hybridization: transporters, signal transduction Rozenn Dalbi?Tran and Pascal Mermilloda
Expression regulated by
LH, Growth Factors/ cytokines
Comment
Reduced neurotrophin receptor tropomyosin-related kinase A expression in human granulosa cells: a novel marker of diminishing ovarian reserve. Buyuk E et al. OBJECTIVE: To determine whether human mural and cumulus granulosa cell neurotrophin and neurotrophin receptor content correlate to ovarian reserve markers. DESIGN: Prospective, laboratory-based study. SETTING: Academic assisted reproductive technology (ART) program. PATIENT(S): Twenty-three women undergoing ART. INTERVENTION(S): Mural and cumulus granulosa cells were collected from women undergoing oocyte retrieval during ART cycles. Relative messenger RNA (mRNA) levels of neurotrophins and their receptors were measured by quantitative reverse transcription-polymerase chain reaction and correlated to serum antim?an hormone (AMH) levels and the number of oocytes retrieved. MAIN OUTCOME MEASURE(S): Number of oocytes retrieved. RESULT(S): Mural and cumulus granulosa cell nerve growth factor receptor tropomyosin-related kinase A (TrkA) mRNA correlated strongly to the number of oocytes retrieved. Similarly, higher serum AMH was associated with higher cumulus granulosa cell TrkA mRNA. Both mural and cumulus granulosa cell p75(NTR)/TrkA ratios were lower in women with higher serum AMH, and the number of oocytes retrieved was greater among women with low p75(NTR)/TrkA ratio. No significant associations were found between brain-derived neurotrophic factor (BDNF) and its specific receptor tropomyosin-related kinase B (TrkB) and ovarian reserve markers. Although BDNF and TrkB expression were higher in cumulus compared with mural granulosa cells, no such association was found between TrkA and granulosa cells. Antim?an hormone and cumulus TrkA mRNA, in a model incorporating both, correlated strongly to the number of oocytes retrieved (R(2) = 0.84). CONCLUSION(S): Cumulus TrkA and p75(NTR) mRNA correlate to ovarian reserve, whereas BDNF and TrkB are associated with the type of granulosa cell.
Ovarian localization
Oocyte, Granulosa, Theca
Comment
Dissen GA, et al.To identify some of the processes that may be affected by trkA activation in the thecal compartment, we used purified thecal cells/thecal fibroblasts from bovine ovaries (heretofore referred to as thecal cells). Ribonuclease protection assays employing bovine-specific cRNA probes demonstrated the presence of the messenger RNAs (mRNAs) encoding NGF and its receptors, p75 NTR and trkA, in the thecal compartment of small, medium, and large antral follicles and showed that trkA mRNA is also expressed in granulosa cells. In situ hybridization and immunohistochemical examination of intact ovaries confirmed these cellular sites of NGF and trkA synthesis.
Immunocytochemical evidence for the presence and location of the neurotrophin-Trk receptor family in adult human preovulatory ovarian follicles. Seifer DB et al. OBJECTIVE: This study was undertaken to evaluate the presence or absence of neurotrophins and their respective receptors within adult human preovulatory follicles. STUDY DESIGN: Prospective study of neurotrophins and their receptors in follicular cells and unfertilized oocytes from women undergoing aspiration for in vitro fertilization/intracytoplasmic sperm injection. Cells (mural and cumulus granulosa cells, unfertilized oocytes) were examined for immunocytochemical staining of neurotrophin and receptor proteins. RESULTS: Mural and cumulus granulosa cells were positive for BDNF, NT-4/5, NT-3, and NGF, as well as for Trk B, Trk C, and Trk A receptors. Unfertilized oocytes were positive for Trk B, Trk C, and Trk A receptors. CONCLUSION: Neurotrophins and their respective receptor proteins are present within the mural and cumulus granulosa cells of adult human preovulatory follicles. Neurotrophin receptors are present in human unfertilized oocytes. The location of the neurotrophins and their receptors suggest both an autocrine and paracrine function within the adult human ovarian follicle.
Nerve Growth Factor Induces Vascular Endothelial Growth Factor Expression in Granulosa Cells via a trkA Receptor/ MAPK-ERK2 dependent pathway. Julio-Pieper M et al. Context: Acquisition of ovulatory competence by antral follicles requires development of an adequate vascular supply. Although it is well established that ovarian angiogenesis is cyclically regulated by vascular endothelial growth factor (VEGF), the factors controlling VEGF production by ovarian follicles remain largely unknown. Nerve growth factor (NGF) may be one of these factors, because NGF promotes angiogenesis and synthesis of angiogenic factors in other tissues and is produced by human granulosa cells (h-GCs). Objective: To determine if NGF influences the production of VEGF by h-GCs and to identify a potential signaling pathway underlying this effect. Design: A prospective experimental study. Patients: H-GCs were obtained from 41 women participating in the in vitro fertilization program of our Institution. Methods: Changes in VEGF mRNA after exposure to NGF were evaluated in cultured h-GCs by PCR and real-time PCR. The effect of NGF on VEGF secretion was determined by ELISA. The involvement of trkA, the high affinity NGF receptor, was examined by inhibiting the receptor's tyrosine kinase activity with K252a. The contribution of an ERK1/ERK2-mediated signaling pathway was identified by detecting NGF-dependent phosphorylation of these proteins and by blocking their activity with the inhibitor U0126. Results: NGF promotes VEGF production in cultured h-GCs. Blockade of trkA receptor tyrosine kinase activity blocks this effect. NGF induces MAPK ERK2 phosphorylation, and blockade of this signaling pathway prevents the NGF-induced increase in VEGF production. Conclusions: NGF promotes ovarian angiogenesis by enhancing the synthesis and secretion of VEGF from h-GCs, via a trkA- and ERK2-dependent mechanism.
Follicle stages
Primary, Secondary, Antral, Preovulatory
Comment
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
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment: TrkA and TrkB receptors facilitate follicle assembly and early follicular development in the mouse ovary. Kerr B et al. Recent studies have demonstrated that neurotrophins (NTs) and their Trk tyrosine kinase receptors, thought to be exclusively required for development of the nervous system, are also involved in controlling ovarian development. Here we show that primordial follicle formation is decreased in the absence of nerve growth factor (NGF) or its receptor TrkA, and in the absence of TrkB, the receptor for neurotrophin-4 (NT4) and brain-derived neurotrophic factor (BDNF). This deficiency is not due to premature oocyte loss, because the ovaries of trkA-/- and trkB-/- mice do not show an increased rate of oocyte death antedating the initiation of folliculogenesis. Moreover, exposure of NGF-deficient ovaries to NGF rescues the defect in follicular assembly, if TrkA receptors are present, suggesting that the absence of neurotrophins causes a delay, and not an irretrievable loss, of follicle formation. Both the number of secondary follicles and FSH receptor (FSHR) expression are diminished in trkA and trkB-null ovaries, but not in ovaries lacking the common NT receptor p75NTR. Transient exposure of wild-type (WT) ovaries to NT4 increases FSHR gene expression and enhances the ability of the ovary to respond to FSH with formation of cyclin D2, a cell-cycle protein mediating the proliferative actions of FSH in the ovary. These results indicate that both TrkA and TrkB receptors are necessary for the timely assembly of primordial follicles and for sustaining early follicular development. They also suggest that a mechanism by which TrkB receptors facilitate subsequent follicle development is by inducing the formation of functional FSHR.