Nerve growth factor receptor (NGFR) is also referred to as p75(NTR) due to its molecular mass and its ability to bind at low affinity not only NGF (see OMIM 162030), but also other neurotrophins, including brain-derived neurotrophic factor (BDNF; 113505), neurotrophin-3 (NTF3; 162660), and neurotrophin-4/5 (NTF5; 162662). At the time of its discovery, NGFR was considered a unique type of protein. Subsequently, however, a large superfamily of tumor necrosis factor receptors were found to share the overall structure of NGFR (4 extracellular ligand-binding, cysteine-rich repeats, or CRs, and signaling through association with, or disassociation from, cytoplasmic interactors). The identification of this superfamily helped elucidate some of the biologic functions of NGFR, including its ultimate involvement in the nuclear factor kappa-B (NFKB; see 164011) and apoptosis pathways. 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; 191315), TRKB (NTRK2; 600456), and TRKC (NTRK3; 191316). TRKA, TRKB, and TRKC are specific for or 'preferred by' NGF, NTF5 and BDNF, and NTF3, respectively . NTF3 also binds to TRKA and TRKB, but with significantly lower affinity.
NCBI Summary:
Nerve growth factor receptor contains an extracellular domain containing four 40-amino acid repeats with 6 cysteine residues at conserved positions followed by a serine/threonine-rich region, a single transmembrane domain, and a 155-amino acid cytoplasmic domain. The cysteine-rich region contains the nerve growth factor binding domain.
General function
Receptor
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.
Cellular localization
Plasma membrane
Comment
Ovarian function
Follicle endowment, Follicle development, Early embryo development
Comment
Role of nerve growth factor (NGF) and its receptors in folliculogenesis. Chaves RN et al. SummaryNerve growth factor (NGF) is a prototype member of the neurotrophins family and has important functions in the maintenance of viability and proliferation of neuronal and non-neuronal cells, such as certain ovarian cells. The present review highlights the role of NGF and its receptors on ovarian follicle development. NGF initiates its multiple actions through binding to two classes of receptors: the high affinity receptor tyrosine kinase A (TrkA) and the low-affinity receptor p75. Different intracytoplasmic signalling pathways may be activated through binding to NGF due to variation in the receptors. The TrkA receptor activates predominantly phosphatidylinositol-3-kinase (PI3K) and mitogenic activated protein kinase (MAPK) to promote cell survival and proliferation. The activation of the phospholipase type C? (PLC?) pathway, which results in the production of diacylglycerol (DAG) and inositol triphosphate (IP3), culminates in the release of calcium from the intracytoplasmic cellular stocks. However, the details of activation through p75 receptor are less well known. Expression of NGF and its receptors is localized in ovarian cells (oocyte, granulosa, theca and interstitial cells) from several species, which suggests that NGF and its receptors may regulate some ovarian functions such as follicular survival or development. Thus, the use of NGF in culture medium for ovarian follicles may be of critical importance for researchers who want to promote follicular development in vitro in the future.
The effect of nerve growth factor on nuclear progression of porcine oocytes during in vitro maturation and embryo development Papp AB, et al .
The present study examined the effect of nerve growth factor (NGF) on in vitro maturation (IVM), in vitro fertilisation (IVF) and subsequent embryonic development of porcine oocytes. Cumulus-oocyte complexes were cultured with or without 1.0 ng/ml NGF for 40 h. After IVF, they were cultured in vitro for 6 days. After 10 and 20 h of IVM, there was no difference in nuclear status between the NGF-treated and control oocytes. Significant differences were detected in nuclear progression of oocytes matured in the presence or absence of NGF at 30 h of culture. A higher proportion of NGF-treated oocytes were at M-II stage compared to the control. Nevertheless, at the end of the 40-h IVM period, there was no difference in the proportion of M-II stage oocytes between the NGF-treated and control groups. NGF in IVM medium did not influence the developmental competence of putative embryos. Most embryos remained at the 2- to 4-cell stage; however, a significant amount of embryos reached the morula stage both in the NGF and the control groups. These results suggest that NGF during IVM accelerates nuclear progression of porcine oocytes by enhancing the post-diakinetic events of meiosis.
Expression regulated by
Comment
Ovarian localization
Oocyte, Granulosa
Comment
Dissen GA, et al reported the expression of neurotrophins and their receptors in the mammalian ovary is developmentally regulated and changes at the time of folliculogenesis.
Neurotrophins initiate their biological effects by binding to cell membrane tyrosine kinase receptors of the trk protooncogene family. In addition, all neurotrophins recognize with similar affinity a different receptor molecule known as p75 nerve growth factor receptor (p75 NGFR) or low affinity NGFR, which appears to interact with the trk receptors to potentiate their response to neurotrophins. The mature mammalian ovary has been shown to synthesize several neurotrophins, including nerve growth factor (NGF), neurotrophin 3 (NT-3), and neurotrophin 4/5 (NT-4/5). The ovary also expresses some of the neurotrophin receptors, including p75 NGFR, trkB [the receptor for NT-4/5 and brain-derived neurotropic factor (BDNF)], and trkA (the NGF receptor). The present experiments were undertaken to determine whether neurotrophins and their receptors are expressed at the time of definitive ovarian histogenesis, and whether any of them exhibit a developmental pattern of expression related to the completion of folliculogenesis. Immunohistochemical identification of p75 NGFR in rat embryonic ovaries revealed that the receptor is predominantly expressed in mesenchymal cells. By gestational day 18, these cells have formed pockets that enclose presumptive pregranulosa cells and groups of oocytes into ovigerous cords. Immediately after birth, the ovigerous cords are subdivided, resulting in the abrupt formation of primordial follicles between 24-48 h after birth. Consistent with these observations, the p75 NGFR messenger RNA (mRNA) content increased after birth and remained elevated at the time of follicular assembly. 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.
Follicle stages
Primordial
Comment
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: fertile Comment: By targeted disruption of exon 3 of the Ngfr gene, Lee et al. (1992) generated mice lacking functional Ngfr. The Ngfr -/- mice were viable and fertile but developed skin defects in all extremities as well as ulcers that were prone to secondary infection with loss of epidermis. Immunohistochemistry revealed a lack of calcitonin gene-related peptide (CALCA; 114130)- and substance P (162320)-expressing peripheral sensory nerve fibers. Mutant mice had a loss of heat sensitivity but no defects in innervation of the iris or salivary gland. Mice carrying a single copy of a human NGFR transgene did not have neuropeptide and sensory loss or the peripheral ulcers.