The Trk family of receptors play a wide variety of roles in physiological and disease processes in both neuronal and non-neuronal tissues. Amongst these the TrkB receptor in particular has attracted major attention due to its critical role in signalling for brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT3) and neurotrophin-4 (NT4). TrkB signalling is indispensable for the survival, development and synaptic plasticity of several subtypes of neurons in the nervous system. Substantial evidence has emerged over the last decade about the involvement of aberrant TrkB signalling and its compromise in various neuropsychiatric and degenerative conditions. Unusual changes in TrkB signalling pathway have also been observed and implicated in a range of cancers. Variations in TrkB pathway have been observed in obesity and hyperphagia related disorders as well. Both BDNF and TrkB have been shown to play critical roles in the survival of retinal ganglion cells in the retina. The ability to specifically modulate TrkB signalling can be critical in various pathological scenarios associated with this pathway. In this review, we discuss the mechanisms underlying TrkB signalling, disease implications and explore plausible ameliorative or preventive approaches.

/pdf/trkb-receptor-signalling-implications-in-neurodegenerative-4spsvplnt7.pdf

TrkB Receptor Signalling: Implications in Neurodegenerative, Psychiatric and Proliferative Disorders

Background Neurotrophins [nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4)] and glial cell line-derived neurotrophic factor (GDNF) are soluble polypeptide growth factors that are widely recognized for their roles in promoting cell growth, survival and differentiation in several classes of neurons. Outside the nervous system, neurotrophin (NT) and GDNF signaling events have substantial roles in various non-neural tissues, including the ovary. Objective and rationale The molecular mechanisms that promote and regulate follicular development and oocyte maturation have been extensively investigated. However, most information has been obtained from animal models. Even though the fundamental process is highly similar across species, the paracrine regulation of ovarian function in humans remains poorly characterized. Therefore, this review aims to summarize the expression and functional roles of NTs and GDNF in human ovarian biology and disorders, and to describe and propose the development of novel strategies for diagnosing, treating and preventing related abnormalities. Search methods Relevant literature in the English language from 1990 to 2018 describing the role of NTs and GDNF in mammalian ovarian biology and phenotypes was comprehensively selected using PubMed, MEDLINE and Google Scholar. Outcomes Studies have shown that the neurotrophins NGF, BDNF, NT-3 and NT-4 as well as GDNF and their functional receptors are expressed in the human ovary. Recently, gathered experimental data suggest putative roles for NT and GDNF signaling in the direct control of ovarian function, including follicle assembly, activation of the primordial follicles, follicular growth and development, oocyte maturation, steroidogenesis, ovulation and corpus luteum formation. Additionally, crosstalk occurs between these ovarian regulators and the endocrine signaling system. Dysregulation of the NT system may negatively affect ovarian function, leading to reproductive pathology (decreased ovarian reserve, polycystic ovary syndrome and endometriosis), female infertility and even epithelial ovarian cancers. Wider implications A comprehensive understanding of the expression, actions and underlying molecular mechanisms of the NT/GDNF system in the human ovary is essential for novel approaches to therapeutic and diagnostic interventions in ovarian diseases and to develop more safe, effective methods of inducing ovulation in ART in the treatment of female infertility.

Neurotrophins and glial cell line-derived neurotrophic factor in the ovary: physiological and pathophysiological implications

Brain-derived neurotrophic factor plasma variation during the different phases of the menstrual cycle in women with premenstrual syndrome

BACKGROUND: The stage of folliculogenesis at which the human zona pellucida (ZP) is initiated and the cells responsible for the origin of the ZP continue to be controversial. This study characterizes the development of the ZP during human folliculogenesis using ovarian samples donated from patients requesting ovarian storage. METHODS: Follicles (from n = 18 patients, 14-40 years old) within fresh tissue and following development in a xenograft system were stained, using immunohistochemical techniques, for the presence of the three human ZP proteins, ZP1, ZP2 and ZP3. Over 500 primordial follicles and >20 follicles at each developmental stage were examined. RESULTS: All three ZP proteins were detected within the oocyte of the primordial follicle. Presence of ZP1 and ZP3 was observed in the majority of primordial oocytes (93% and 95%, respectively), whereas ZP2 was detected in only 32% of these follicles. The three ZP proteins were detected in the cytoplasm of cuboidal granulosa cells and their distribution correlates with developmental stages throughout folliculogenesis. CONCLUSIONS: ZP proteins were detected in both the oocyte and the granulosa cells as early as the primordial follicle stage in the human. The detection of ZP proteins in the quiescent primordial follicle suggests that these proteins have been present since oogenesis.

/pdf/detection-of-zona-pellucida-proteins-during-human-5gjgtz84hz.pdf

Detection of zona pellucida proteins during human folliculogenesis

Premature ovarian failure (POF) is a leading cause of women's infertility without effective treatment. Here we show that intravenous injection of Ab4B19, an agonistic antibody for the BDNF receptor TrkB, penetrates into ovarian follicles, activates TrkB signaling, and promotes ovary development. In both natural aging and cyclophosphamide-induced POF models, treatment with Ab4B19 completely reverses the reduction of pre-antral and antral follicles, and normalizes gonadal hormone. Ab4B19 also attenuates gonadotoxicity and inhibits apoptosis in cyclophosphamide-induced POF ovaries. Further, treatment with Ab4B19, but not BDNF, restores the number and quality of oocytes and enhances fertility. In human, BDNF levels are high in granulosa cells and TrkB levels increase in oocytes as they mature. Moreover, BDNF expression is down-regulated in follicles of aged women, and Ab4B19 activates TrkB signaling in human ovary tissue ex vivo. These results identify TrkB as a potential target for POF with differentiated mechanisms, and confirms superiority of TrkB activating antibody over BDNF as therapeutic agents. 

/pdf/trkb-agonist-antibody-ameliorates-fertility-deficits-in-aged-1ympmrv9.pdf

TrkB agonist antibody ameliorates fertility deficits in aged and cyclophosphamide-induced premature ovarian failure model mice

The signals initiating the growth of primordial follicles are unknown. Growth factors such as neurotrophin 4/5 (NT-4/5) and brain-derived neurotrophic factor (BDNF) may play a role in this process. To investigate the expression of NT-4/5 and BDNF and their receptor tyrosine kinase B (TrkB) in the early developing follicles, we fixed and froze 12 ovarian samples from adolescents/ adults and 31 ovaries from human fetuses. The fixed samples were prepared for immunohistochemical staining for NT-4/5, BDNF and the TrkB receptor. Total RNA was extracted from the frozen ovarian samples, and the expression of NT-4/5, BDNF and the TrkB receptor (full length and two truncated isoforms) was investigated by RT–PCR. Products were resolved by 1% agarose gel electrophoresis and image analysis. Immunohistochemical staining revealed the expression of NT-4/5 and BDNF mainly in oocytes and, in a minority of samples, also in the granulosa cells (GCs); TrkB receptor was identified in oocytes and GCs. Transcripts of NT-4/5, BDNF and all forms of TrkB receptor were identified in the samples. To elucidate whether indeed NT-4/5 and BDNF are involved in growth initiation of human primordial follicles, they should be added to the culture medium.

Tyrosine kinase B receptor and its activated neurotrophins in ovaries from human fetuses and adults

/pdf/session-58-fertility-preservation-2-573zvp0xcg.pdf

Session 58: Fertility Preservation 2

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Tyrosine kinase B receptor and its activated neurotrophins in ovaries from human fetuses and adults

Session 58: Fertility Preservation 2