NGF and other neurotrophins, including brain-derived
neurotrophic factor (BDNF; OMIM 113505), neurotrophin-3 (NTF3; OMIM 162660), and neurotrophin-4/5 (NTF5; 162662) are important in the development of neuronal and other tissues.
Neurotrophin-5 (NTF5 or NT5) has been also referred to as neurotrophin-4 (NTF4 or NT4). The confusion over the nomenclature of this factor arose because this mammalian neurotrophin is much
more divergent from its amphibian counterpart (NT4) than are the other members of the family; hence the designation
'neurotrophin-5.' Subsequent studies demonstrated a functional correspondence between this protein and the amphibian
NT4 protein. Some laboratories adopted the nomenclature 'neurotrophin-4/5' to denote the mammalian counterpart of
Xenopus NT4.
NCBI Summary:
This gene is a member of a family of neurotrophic factors, neurotrophins, that control survival and differentiation of mammalian neurons. The expression of this gene is ubiquitous and less influenced by environmental signals. While knock-outs of other neurotrophins including nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 prove lethal during early postnatal development, NTF5-deficient mice only show minor cellular deficits and develop normally to adulthood. [provided by RefSeq, Jul 2008]
Single-cell transcriptome and cell-specific network analysis reveal the reparative effect of neurotrophin-4 in preantral follicles grown in vitro. Guo Y et al. (2021) In-vitro-grow (IVG) of preantral follicles is essential for female fertility preservation, while practical approach for improvement is far from being explored. Studies have indicated that neurotrophin-4 (NT-4) is preferentially expressed in human preantral follicles and may be crucial to preantral follicle growth. We observed the location and expression of Tropomyosin-related kinase B (TRKB) in human and mouse ovaries with immunofluorescence and Western blot, and the relation between oocyte maturation and NT-4 level in follicular fluid (FF). Mice model was applied to investigate the effect of NT-4 on preantral follicle IVG. Single-cell RNA sequencing of oocyte combined with cell-specific network analysis was conducted to uncover the underlying mechanism of effect. We reported the dynamic location of TRKB in human and mouse ovaries, and a positive relationship between human oocyte maturation and NT-4 level in FF. Improving effect of NT-4 was observed on mice preantral follicle IVG, including follicle development and oocyte maturation. Transcriptome analysis showed that the reparative effect of NT-4 on oocyte maturation might be mediated by regulation of PI3K-Akt signaling and subsequent organization of F-actin. Suppression of advanced stimulated complement system in granulosa cells might contribute to the improvement. Cell-specific network analysis revealed NT-4 may recover the inflammation damage induced by abnormal lipid metabolism in IVG. Our data suggest that NT-4 is involved in ovarian physiology and may improve the efficiency of preantral follicle IVG for fertility preservation.//////////////////
Paredes A, et al reported that TrkB receptors are required for follicular growth and oocyte survival in the mammalian ovary.
Although it is well established that both follicular assembly and the initiation of follicle growth in the mammalian ovary occur independently of pituitary hormone support, the factors controlling these processes remain poorly understood. The atuhors now report that neurotrophins (NTs) signaling via TrkB receptors are required for the growth of newly formed follicles. Both neurotrophin-4/5 (NT-4) and brain-derived neurotrophic factor (BDNF), the preferred TrkB ligands, are expressed in the infantile mouse ovary. Initially, they are present in oocytes, but this site of expression switches to granulosa cells after the newly assembled primordial follicles develop into growing primary follicles. Full-length kinase domain-containing TrkB receptors are expressed at low and seemingly unchanging levels in the oocytes and granulosa cells of both primordial and growing follicles. In contrast, a truncated TrkB isoform lacking the intracellular domain of the receptor is selectively expressed in oocytes, where it is targeted to the cell membrane as primary follicles initiate growth. Using gene-targeted mice lacking all TrkB isoforms, we show that the ovaries of these mice or those lacking both NT-4 and BDNF suffer a stage-selective deficiency in early follicular development that compromises the ability of follicles to grow beyond the primary stage. Proliferation of granulosa cells-required for this transition-and expression of FSH receptors (FSHR), which reflects the degree of biochemical differentiation of growing follicles, are reduced in trkB-null mice. Ovaries from these animals grafted under the kidney capsule of wild-type mice fail to sustain follicular growth and show a striking loss of follicular organization, preceded by massive oocyte death. These results indicate that TrkB receptors are required for the early growth of ovarian follicles and that they exert this function by primarily supporting oocyte development as well as providing granulosa cells with a proliferative signal that requires oocyte-somatic cell bidirectional communication. The predominance of truncated TrkB receptors in oocytes and their developmental pattern of subcellular expression suggest that a significant number of NT-4/BDNF actions in the developing mammalian ovary are mediated by these receptors.
Gene whose expression is detected by cDNA array hybridization: transcription factors, cell signaling and extracellular communication Rozenn Dalbis-Tran and Pascal Mermilloda
Expression regulated by
Comment
Ovarian localization
Oocyte, Granulosa
Comment
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.
Follicle stages
Secondary, Antral
Comment
Anderson RA, et al 2002 reported that neurotropins and their receptors are expressed in the human
fetal ovary. The neurotropins are survival and differentiation factors
in the nervous system, acting via high affinity receptors of the trk
protooncogene family and the low affinity p75 nerve growth factor receptor,
and have also been described in the rodent ovary, where changes in NT4/TrkB
gene expression have been detected at the time of primordial follicle
formation. There are no data on neurotropin expression in the normal human
ovary. The athors have investigated the expression and localization of neurotropins
and their receptors in the midtrimester human fetal ovary (13-21 wk
gestation). Expression of mRNA for neurotropins and their receptors was
detected by RT-PCR. Clusters of oogonia were found to be the predominant site
of NT4 mRNA expression using in situ hybridization. However, at later
gestations granulosa cells of primordial follicles showed increased
expression, with lesser expression in the enclosed oocytes. NT4 protein was
also localized to the granulosa cells by immunohistochemistry and at earlier
developmental stages to epithelioid cells, which were mingled with clusters of
oogonia not expressing NT4. TrkB receptor protein was localized by
immunohistochemistry to germ cells at all gestations examined. The p75 nerve
growth factor receptor protein was exclusively expressed in the ovarian
stroma. These data demonstrate the expression of neurotropins and their
receptors within the human fetal ovary. Developmental changes in the pattern
of expression of NT4 around the time of primordial follicle formation suggest
that neurotropins may be involved in signaling between somatic cells and germ
cells at this crucial stage of ovarian development.
Phenotypes
Mutations
2 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment:Ojeda SR, et al 2000 reported that neurotrophic and cell-cell dependent control of early follicular
development.
Neurotrophins (NTs) and their receptors play an essential role in the
differentiation and survival of defined neuronal populations of the central and
peripheral nervous systems. Their actions, however, do not appear to be limited
to the nervous system, as both NTs and their receptors have been found in non
neuronal cells, including cells of the endocrine system. At least four of the five
known neurotrophins, including nerve growth factor (NGF), brain-derived
neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4),
and their receptors (p75 NTR, trkA, trkB and trkC) are present in the developing
ovary. Using mice carrying null mutations of the genes encoding neurotrophins
(NGF, NT-4, BDNF) or the receptor that mediates the actions of NT-4 and BDNF
(trkB), the authors have obtained initial results consistent with the notion that
neurotrophins are required for the growth of primordial follicles. NGF-deficient
mice show a decreased formation of both primary and secondary preantral
follicles. Null mutation of the NT-4 gene failed to affect either folliculogenesis or
follicular development. However, formation of primary and secondary follicles
was compromised in mice carrying a null mutation of both the NT-4 and BDNF
genes, suggesting compensation of function by BDNF in NT-4 knockouts. Support
for this concept is provided by the similar deficiency in follicular growth
observed in animals carrying a null mutation of the gene encoding trkB, the
receptors mediating NT-4 and BDNF actions.
Species: mouse
Mutation name: None
type: null mutation fertility: infertile - ovarian defect Comment:Paredes A, et al reported that TrkB receptors are required for follicular growth and oocyte survival in the mammalian ovary.
Although it is well established that both follicular assembly and the initiation of follicle growth in the mammalian ovary occur independently of pituitary hormone support, the factors controlling these processes remain poorly understood. The atuhors now report that neurotrophins (NTs) signaling via TrkB receptors are required for the growth of newly formed follicles. Both neurotrophin-4/5 (NT-4) and brain-derived neurotrophic factor (BDNF), the preferred TrkB ligands, are expressed in the infantile mouse ovary. Initially, they are present in oocytes, but this site of expression switches to granulosa cells after the newly assembled primordial follicles develop into growing primary follicles. Full-length kinase domain-containing TrkB receptors are expressed at low and seemingly unchanging levels in the oocytes and granulosa cells of both primordial and growing follicles. In contrast, a truncated TrkB isoform lacking the intracellular domain of the receptor is selectively expressed in oocytes, where it is targeted to the cell membrane as primary follicles initiate growth. Using gene-targeted mice lacking all TrkB isoforms, we show that the ovaries of these mice or those lacking both NT-4 and BDNF suffer a stage-selective deficiency in early follicular development that compromises the ability of follicles to grow beyond the primary stage. Proliferation of granulosa cells-required for this transition-and expression of FSH receptors (FSHR), which reflects the degree of biochemical differentiation of growing follicles, are reduced in trkB-null mice. Ovaries from these animals grafted under the kidney capsule of wild-type mice fail to sustain follicular growth and show a striking loss of follicular organization, preceded by massive oocyte death. These results indicate that TrkB receptors are required for the early growth of ovarian follicles and that they exert this function by primarily supporting oocyte development as well as providing granulosa cells with a proliferative signal that requires oocyte-somatic cell bidirectional communication. The predominance of truncated TrkB receptors in oocytes and their developmental pattern of subcellular expression suggest that a significant number of NT-4/BDNF actions in the developing mammalian ovary are mediated by these receptors.