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

Abstract

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.

Keywords: brain-derived neurotrophic factor; diminished ovarian reserve; endometriosis; female infertility; follicular development; glial cell line-derived neurotrophic factor; nerve growth factor; neurotrophins; polycystic ovary syndrome.

Figure 1

Schematic representation of the human GDNF gene and two splicing protein isoforms. The human glial cell line-derived neurotrophic factor (GDNF) gene has six exons (color boxes represent exons, although not to scale) that encode the pre- α-pro-GDNF isoform with a full-length 58 amino acid pro-region and the pre-β-pro-GDNF isoform with a shorter 32 amino acid pro-region. Adapted from (Penttinen et al., 2018).

Figure 2

Neurotrophin receptors and their downstream signaling pathways. NGF binds to TrkA, BDNF and NT-4 bind to TrkB, and NT-3 binds to TrkC, which further induces the activation of Ras/MAPK, PLCγ1 and PI3K/Akt pathways. All neurotrophins (NGF, BDNF, NT-3 and NT-4) also bind to p75NTR receptor, which initiates the recruitment of various adaptors that further activate NF-κB and JNK pathways. BDNF, brain-derived neurotrophic factor; JNK, Jun kinase; MAPK, mitogen-activated protein kinase; NGF, nerve growth factor; NT-3, neurotrophin-3; NT-4, neurotrophin-4; NF-κB, nuclear factor-κB; PI3K, Phosphatidylinositol-3-kinase; PLCγ1, phospholipase Cγ1.

Figure 3

Immunohistochemical staining of NGF, BDNF and GDNF in the human ovary. All sections were stained with the immunoperoxidase staining and then counterstained with Mayer’s haematoxylin. (A) Section of a human ovary from a 38-year-old woman. NGF is expressed in granulosa cells of the primordial follicle, and there is partial staining (with positive nuclear staining) in the oocyte. Original magnification X400. Reprinted with permissions from Abir et al. (2005). (B) Section of a human ovary from a 16-year-old girl. BDNF is expressed in the secondary (arrow) and primordial (arrow head) follicles. Original magnification X400. Reprinted with permissions from Streiter et al. (2016). (C) Section of a human ovary from a 22-year-old woman. GDNF is expressed in the oocytes and a portion of the granulosa cells and stroma cells. Original magnification X400. Reprinted with permissions from Farhi et al. (2010).

Figure 4

Schematic showing the neurotrophic factors involved in regulation of ovarian folliculogenesis. Neurotrophins, including NGF (in red), BDNF (in green), NT-3 (in purple), NT-4 (in yellow-brown), as well as GDNF (in blue), participate in and regulate follicular development at each of the defined stages throughout folliculogenesis, including follicle assembly, primordial follicle activation, follicular growth, steroidogenesis, oocyte maturation, ovulation and corpus luteum formation. Solid lines following each neurotrophic factor represent data obtained from studies in humans, while dashed lines represent data obtained from animal models.