Because of the close amino acid and nucleotide sequence similarity of nerve growth factor (NGF; OMIM:162030) and
brain-derived neurotrophic factor (BDNF; OMIM:113505), Jones and Reichardt (1990) suspected that these neurotrophic
factors are part of a larger gene family and searched for other members of the family by a screen involving the
polymerase chain reaction (PCR) and low stringency hybridization with degenerate oligonucleotides. In this way, they
identified a third gene, neurotrophin-3, that is closely related to both NGF and BDNF.
NCBI Summary:
The protein encoded by this gene is a member of the neurotrophin family, that controls survival and differentiation of mammalian neurons. This protein is closely related to both nerve growth factor and brain-derived neurotrophic factor. It may be involved in the maintenance of the adult nervous system, and may affect development of neurons in the embryo when it is expressed in human placenta. NTF3-deficient mice generated by gene targeting display severe movement defects of the limbs. The mature peptide of this protein is identical in all mammals examined including human, pig, rat and mouse.
General function
Ligand, Growth factor
Comment
Cellular localization
Secreted
Comment
Ovarian function
Follicle development, Initiation of primordial follicle growth
Comment
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.
Expression regulated by
Comment
Ovarian localization
Oocyte, Granulosa
Comment
Expression of neurotrophin 3 and its tropomyosin-related kinase receptor C in?human?preantral follicles. Oron G et al. OBJECTIVE: To investigate the expression of neurotrophin 3 (NT3) and its receptor tropomyosin-related kinase C?(TrkC) in human preantral follicles. Neurotrophins appear to play important roles in preantral follicles. Data on ovarian NT3 and its receptor TrkC are sparse in humans. DESIGN: Immunohistochemical, in situ hybridization, and reverse transcriptase polymerase chain reaction study of the expression of the NT3 system in human ovaries. SETTING: Major tertiary-care academic center. PATIENT(S): Fifteen patients who underwent pregnancy terminations and 36 girls and women who underwent laparoscopies for ovarian surgery. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Laboratory analysis of human ovaries. RESULT(S): NT3 protein staining was identified in oocytes and granulosa cells (GCs) of all samples tested. TrkC protein staining was present in oocytes and GCs of the majority of the fetal samples and in oocytes and GCs of all samples from girls and women. The messenger RNA transcripts for the full-length TrkC isoform were identified in oocytes of the majority of the fetal samples, in all the samples from the girls and women, and in GCs from the girls and women. The two NT3 isoforms and the three TrkC isoforms were identified by reverse transcription polymerase chain reaction in all ovarian extracts. CONCLUSION(S): The presence of NT3 and its TrkC receptor in human preantral follicles, and specifically in GCs, suggests that NT3 may be involved in early folliculogenesis, particularly in the activation of primordial follicles.
Dissen GA, et al 1995 reported the expression of neurotrophins and their receptors in the
mammalian ovary is developmentally regulated and changes at the
time of folliculogenesis.
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. In
contrast to the drop in NGF and trkA mRNA expression, NT-4 mRNA levels
increased at the time of follicular assembly, coinciding with the abrupt
appearance of trkB mRNA. In situ hybridization showed that the increase in NT-4
mRNA expression occurred in a subpopulation of oocytes between 24-48 h after
birth, and that the trkB gene became predominantly expressed at this time in
epithelial pregranulosa cells. Substantial, but unchanging, levels of NT-3 mRNA
and the mRNA encoding trkC, the preferred NT-3 receptor, were detected
throughout the perinatal period examined.
Follicle stages
Primordial, Primary, Secondary, Antral
Comment
Expression of neurotrophin 3 and its tropomyosin-related kinase receptor C in?human?preantral follicles. Oron G et al. OBJECTIVE: To investigate the expression of neurotrophin 3 (NT3) and its receptor tropomyosin-related kinase C?(TrkC) in human preantral follicles. Neurotrophins appear to play important roles in preantral follicles. Data on ovarian NT3 and its receptor TrkC are sparse in humans. DESIGN: Immunohistochemical, in situ hybridization, and reverse transcriptase polymerase chain reaction study of the expression of the NT3 system in human ovaries. SETTING: Major tertiary-care academic center. PATIENT(S): Fifteen patients who underwent pregnancy terminations and 36 girls and women who underwent laparoscopies for ovarian surgery. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Laboratory analysis of human ovaries. RESULT(S): NT3 protein staining was identified in oocytes and granulosa cells (GCs) of all samples tested. TrkC protein staining was present in oocytes and GCs of the majority of the fetal samples and in oocytes and GCs of all samples from girls and women. The messenger RNA transcripts for the full-length TrkC isoform were identified in oocytes of the majority of the fetal samples, in all the samples from the girls and women, and in GCs from the girls and women. The two NT3 isoforms and the three TrkC isoforms were identified by reverse transcription polymerase chain reaction in all ovarian extracts. CONCLUSION(S): The presence of NT3 and its TrkC receptor in human preantral follicles, and specifically in GCs, suggests that NT3 may be involved in early folliculogenesis, particularly in the activation of primordial follicles.
Ernfors P, et al 1990 reported that mRNA for neurotrophic factor (HDNF/NT-3) in secondary and tertiary follicles in the ovary.
Cells expressing mRNA for hippcampus-derived neurotrophic factor
(HDNF/NT-3) or brain-derived neurotrophic factor (BDNF) were identified by in
situ hybridization.
Neurotrophin-4/5 and neurotrophin-3 are present within the human ovarian follicle but appear to have different paracrine/autocrine functions.
Seifer DB, et al .
Neurotrophins are a family of soluble polypeptide growth factors widely recognized for their role in the mammalian nervous system. We first reported the unique presence of one neurotrophin, brain-derived neurotrophic factor (BDNF), in the follicular fluid of the human ovarian follicle. The BDNF receptor, Trk B, was identified in mouse oocytes, and BDNF accelerated first polar body extrusion in vitro. In the present study, we examined human follicular fluid and mouse immature oocytes to determine whether another Trk B ligand, neurotrophin-4/5 (NT-4/5), is present within the ovarian follicle and if so, whether it demonstrates activity similar to that of BDNF. We also examined whether a non-Trk B neurotrophin ligand, neurotrophin-3 (NT-3), is present within the follicle and has a possible role in oocyte maturation. NT-4/5 and NT-3 were noted to be present in all human follicular fluid samples aspirated from follicles of women undergoing in vitro fertilization. NT-4/5, but not NT-3, significantly promoted mouse oocyte polar body extrusion. Trk C receptors were not noted to be present in mouse oocytes. This study demonstrates for the first time that NT-4/5 and NT-3 are present in the follicular fluid of the human ovary. These data suggest that NT-4/5, like BDNF, promotes oocyte nuclear maturation. In contrast, NT-3 does not promote oocyte maturation but may contribute to follicle-oocyte maturation by mechanisms not yet identified.