Review

Functions of the neurotrophins during nervous system development: What the knockouts are teaching us

Female reproductive efficiency is influenced by the outcomes of various processes, including folliculogenesis, apoptosis, response to gonadotropin signaling, oocyte maturation, and ovulation. The role of hormones in regulating these processes and other reproductive activities has been well established. It is becoming increasingly evident that in addition to well-characterized hormones, growth factors play vital roles in regulating some of these reproductive activities. Growth factors and their receptors are widely distributed in vertebrate ovaries at different stages of ovarian development, indicating their involvement in intraovarian reproductive functions. In the ovary, cell surface receptors allow growth factors to regulate intraovarian reproductive activities. Understanding these actions in the reproductive axis would provide a tool to target growth factors and/or their receptors to yield desirable reproductive outcomes. These include enrichment of in vitro maturation and fertilization culture media, and management of infertility. This review discusses some widely characterized growth factors belonging to the TGF, EGF, IGF, FGF, and BDNF family of peptides and their role in female reproduction in vertebrates, with a focus on mammals.

NGF, also known as nerve growth factor, is crucial for the survival and differentiation of the nervous system, in addition to being involved in a number of non-neuronal systems. The aim of this work was to investigate the immunolocalization and expression patterns of NGF, its receptor, tyrosine kinase receptor A (TrkA), and p75 in the scent glands of muskrats (Ondatra zibethicus) throughout the breeding and non-breeding seasons. The scent gland mass showed considerable seasonal variations, with higher values during the breeding season and comparatively lower levels during the non-breeding season. While no immunostaining was observed in the interstitial cells, NGF, TrkA, and p75 were immunolocalized in the scent glandular cells and epithelial cells during both breeding and non-breeding seasons. NGF, TrkA, and p75 protein and mRNA expression levels were higher in the scent glands during breeding season compared to the non-breeding season. Circulating levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), and T in the scent gland were all significantly higher throughout the breeding season. The relative levels of the hormones in the plasma and the scent glands as well as NGF, TrkA, and p75 were positively associated with each other. Additionally, transcriptome analysis of the scent glands revealed that differentially expressed genes may be linked to steroid biosynthesis, the estrogen signaling pathway, and neurotransmitter transmembrane transporter function. These results suggest a potential role for NGF, TrkA, and p75 in controlling seasonal variations in the muskrats' scent gland functioning.

Receptor tyrosine kinases (RTKs) are a diverse family of proteins that carry extracellular signals inside cells and affect critical physiological processes such as cell division, survival, proliferation, apoptosis, differentiation, and migration. They are prevalent in the nervous system and can control glial and neuronal activity. RTKs are thus thought to be highly “druggable” targets for treating various illnesses, including cancer. They are implicated in neurodegenerative and psychiatric diseases like depression and addiction. Human genome analysis for tyrosine kinases revealed 90 distinct kinase genes distributed across 20 subfamilies of 58 receptor-type tyrosine kinases and 10 subfamilies of 32 non-RTKs. The complex interplay between their genetic up- and downregulation plays a crucial role in governing the pathophysiology of diseases. This chapter investigates different RTK genes, their mechanism of gene regulation and expression, and the regulation of their activity modulating the downstream effector signaling pathways in neurodegenerative and psychiatric disorders.

The glial cell of the peripheral nervous system (PNS), the Schwann cell (SC), counts among the most multifaceted cells of the body. During development, SCs secure neuronal survival and participate in axonal path finding. Simultaneously, they orchestrate the architectural set up of the developing nerves, including the blood vessels and the endo-, peri- and epineurial layers. Perinatally, in rodents, SCs radially sort and subsequently myelinate individual axons larger than 1 μm in diameter, while small calibre axons become organised in non-myelinating Remak bundles. SCs have a vital role in maintaining axonal health throughout life and several specialized SC types perform essential functions at specific locations, such as terminal SC at the neuromuscular junction (NMJ) or SC within cutaneous sensory end organs. In addition, neural crest derived satellite glia maintain a tight communication with the soma of sensory, sympathetic, and parasympathetic neurons and neural crest derivatives are furthermore an indispensable part of the enteric nervous system. The remarkable plasticity of SCs becomes evident in the context of a nerve injury, where SC transdifferentiate into intriguing repair cells, which orchestrate a regenerative response that promotes nerve repair. Indeed, the multiple adaptations of SCs are captivating, but remain often ill-resolved on the molecular level. Here, we summarize and discuss the knowns and unknowns of the vast array of functions that this single cell type can cover in peripheral nervous system development, maintenance, and repair.

Exposure to traumatic experience represents one of the key environmental factors influencing the risk for several psychiatric disorders, in particular when suffered during childhood, a critical period for brain development, characterized by a high level of neuroplasticity. Abnormalities affecting neurotrophic factors might play a fundamental role in the link between childhood trauma (CT) and early life stress (ELS) and psychiatric disorders.

A systematic review was conducted, considering genetic, biochemical and expression studies along with cognitive and brain structure imaging investigations, based on PubMed and Web of Science databases (available up until November 2021), to identify potential neuroplasticity related biomarkers associated both with CT/ELS and psychiatric disorders. The search was followed by data abstraction and study quality assessment (Newcastle-Ottawa Scale).

103 studies met our eligibility criteria. Among them, 65 were available for genetic, 30 for biochemical and 3 for mRNA data; 45 findings were linked to specific symptomatology/pathologies, 16 with various cognitive functions, 19 with different brain areas, 6 on methylation and 36 performed on control subjects for the Brain Derived Neurotrophic Factor (BDNF); whereas 4 expression/biochemical studies covered Neurotrophin 4 (NT-4), Vascular Endothelium Growth Factor (VEGF), Epidermal Growth Factor (EGF), Fibroblast Growth Factor (FGF), and Transforming Growth Factor β1 (TGF-β1).

Heterogeneity of assessments (biological, psychological, of symptomatology, and CT/ELS), age range and ethnicity of samples for BDNF studies; limited studies for other neurotrophins.

Results support the key role of BDNF (in form of Met allele) as biomarker, both at genetic and biochemical level, in mediating the effect of CT/ELS in psychiatric disorders, passing through specific cognitive functions and specific brain region architecture.

NTRK fusions are rare oncogenic drivers that occur across a range of pediatric cancers. These include infantile fibrosarcoma and secretory breast cancer in which such fusions are nearly pathognomonic, and a spectrum of more common pediatric cancers in which NTRK fusions occur at a lower frequency. Within the last 5 years, two TRK inhibitors, larotrectinib and entrectinib, have demonstrated histology-agnostic activity against NTRK fusion driven cancers and achieved FDA approval. Here the data supporting the use of these TRK inhibitors for the treatment of cancers harboring NTRK fusions is reviewed, with a particular focus on the pediatric experience. Mechanisms of acquired resistance to these first generation TRK inhibitors are discussed and investigational second generation TRK inhibitors that may overcome some of these mechanisms of resistance are highlighted.