Neurotrophic Factor Regulation in Ovarian Development

Neurotrophic factors, traditionally recognised for their roles in neuronal survival and differentiation, have emerged as pivotal regulators of ovarian physiology. Within the ovary, neurotrophins such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4) interact with high-affinity tropomyosin-related kinase (Trk) receptors and the low-affinity p75NTR receptor to orchestrate folliculogenesis, steroidogenesis and oocyte maturation. From the earliest primordial follicles, NGF–TrkA signalling facilitates the acquisition of follicle-stimulating hormone (FSH) receptor expression and thereby confers gonadotropin responsiveness. Subsequent stages of follicle growth rely on BDNF–TrkB and NT-4–TrkB pathways to promote granulosa cell proliferation, enhance oestrogen and progesterone production and support cumulus-oocyte communications. Intracellular cascades such as PI3K–Akt, MAPK–ERK and cyclin-linked CREB activation underpin these effects. Dysregulation of neurotrophic signalling has been implicated in premature ovarian failure, polycystic ovary syndrome and age-related decline in ovarian reserve. The capacity to modulate neurotrophin receptors or local ligand availability offers promising avenues for fertility preservation, rejuvenation of aged ovaries and improvement of assisted-reproduction outcomes. Emerging evidence also highlights microRNA-mediated control of neurotrophin expression within the follicular microenvironment, suggesting novel biomarkers and therapeutic targets for ovarian health across the reproductive lifespan.

Research from Nature Portfolio

Recent studies have demonstrated that an agonistic antibody targeting TrkB effectively penetrates ovarian follicles, activates TrkB signalling and reverses follicular depletion in models of natural ageing and chemotherapy-induced ovarian failure. This approach restores pre-antral and antral follicle numbers, normalises gonadal hormones and improves oocyte quality, surpassing the efficacy of native BDNF. In human ovarian tissues ex vivo, TrkB activation by the antibody re-establishes downstream pathways and supports oocyte maturation. In parallel, investigations in human granulosa-like tumour cells have shown that BDNF stimulates estradiol and progesterone production by upregulating FSH receptor expression and engaging the cAMP–PKA–CREB cascade. These findings underline the therapeutic potential of selectively modulating neurotrophin receptor activities to enhance ovarian function.

Neurotrophic Factor Regulation in Ovarian Development publication trend

The graph below shows the total number of articles in neurotrophic factor regulation in ovarian development across all publications each year (not limited to Nature Index journals).

Technical terms

Neurotrophic factor: Secreted proteins (e.g. NGF, BDNF, NT-4) that bind Trk or p75NTR receptors to regulate cell survival, growth and differentiation beyond the nervous system.

Trk receptor: A family of receptor tyrosine kinases (TrkA, TrkB, TrkC) that mediate high-affinity neurotrophin signalling and activate intracellular pathways.

p75NTR: A low-affinity neurotrophin receptor that modulates Trk receptor function and can influence cell survival or apoptosis.

Folliculogenesis: The sequential maturation of ovarian follicles from dormant primordial to ovulatory stages.

Granulosa cell: Somatic cells surrounding the oocyte, essential for hormone synthesis and paracrine support.

Primordial follicle: The earliest stage of follicle development, comprising an immature oocyte enveloped by flattened granulosa cells.

Steroidogenesis: The enzymatic process by which cholesterol is converted into steroid hormones, including oestrogen and progesterone.

References

1. BDNF promotes mouse follicular development and reverses ovarian aging by promoting cell proliferation. Journal of Ovarian Research (2023).
2. TrkB agonist antibody ameliorates fertility deficits in aged and cyclophosphamide-induced premature ovarian failure model mice. Nature Communications (2022).
3. Brain-derived neurotrophic factor promotes human granulosa-like tumor cell steroidogenesis and proliferation by activating the FSH receptor-mediated signaling pathway. Scientific Reports (2017).
4. Nerve growth factor induces the expression of functional FSH receptors in newly formed follicles of the rat ovary.. Endocrinology (2002).
5. Roles of miR-10a-5p and miR-103a-3p, Regulators of BDNF Expression in Follicular Fluid, in the Outcomes of IVF-ET. Frontiers in Endocrinology (2021).