The nerve growth factor protein family is generally referred to as the neurotrophin family, a group of structurally and evolutionarily related secreted growth factors that play essential roles in nervous-system development, neuronal survival, axonal and dendritic growth, synapse formation, and activity-dependent neural plasticity. The classical mammalian neurotrophins comprise nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4, also known as NT-4/5). These proteins are initially synthesized as precursor molecules, or proneurotrophins, which can subsequently undergo intracellular or extracellular proteolytic processing to generate biologically active mature neurotrophins. Mature neurotrophins generally interact with their cell-surface receptors as non-covalent homodimers.

The biological actions of neurotrophins are mediated primarily by the tropomyosin receptor kinase (Trk) family of receptor tyrosine kinases and the p75 neurotrophin receptor (p75NTR). NGF preferentially binds TrkA (NTRK1), whereas BDNF and NT-4/5 primarily activate TrkB (NTRK2). NT-3 preferentially binds TrkC (NTRK3), although it can also activate TrkA or TrkB in particular cellular contexts. Ligand binding induces Trk receptor dimerization and phosphorylation of intracellular tyrosine residues, thereby activating major downstream signalling pathways including Ras–MAPK, PI3K–AKT, and PLCγ. Collectively, these pathways regulate neuronal survival, differentiation, neurite growth, synaptic transmission, and gene expression. Following receptor activation, neurotrophin–Trk signalling complexes can also undergo retrograde axonal transport to neuronal cell bodies, allowing locally produced target-derived signals to regulate neuronal survival and transcriptional programmes over long distances.

p75NTR belongs to the tumour necrosis factor receptor superfamily and can interact with multiple mature neurotrophins as well as form receptor complexes with Trk receptors and co-receptors such as sortilin. The biological consequences of p75NTR signalling are highly context dependent. Depending on receptor composition and cellular state, p75NTR can participate in neuronal survival, axonal growth, and synaptic remodelling, but it can also promote growth-cone collapse or cell death under specific conditions. In particular, incompletely processed proneurotrophins such as proNGF and proBDNF can signal through p75NTR–sortilin receptor complexes and produce biological effects that differ substantially from those of their mature counterparts. Neurotrophin activity is therefore determined not only by ligand concentration but also by the relative abundance of precursor and mature forms, receptor composition, cell type, and the local extracellular environment.

Individual neurotrophins exhibit partially distinct physiological functions. NGF is particularly important for the development and maintenance of peripheral sympathetic neurons and subsets of sensory neurons and can enhance the sensitivity of nociceptive neurons, thereby contributing to inflammatory and chronic pain. BDNF is widely expressed throughout the central nervous system and is a major regulator of synaptic plasticity, long-term potentiation, learning, and memory. NT-3 contributes to the development and connectivity of proprioceptive neurons, sensory ganglia, and several other neuronal populations in both the central and peripheral nervous systems. NT-4/5 signals predominantly through TrkB and has functions that partially overlap with, but are spatially and temporally distinct from, those of BDNF. Dysregulation of neurotrophin and neurotrophin-receptor signalling has been associated with neurodegenerative disorders, neural injury, chronic pain, and several psychiatric and neurodevelopmental conditions. Because of their potent neuroprotective and plasticity-promoting properties, NGF, BDNF, and Trk receptors have long been investigated as therapeutic targets for neurological diseases. However, their clinical translation remains challenging owing to limitations associated with blood–brain barrier penetration, protein stability, efficient tissue-specific delivery, and the pleiotropic biological effects of neurotrophin-receptor signalling.

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References

1. Park H, Poo MM. Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci. 2013 Jan;14(1):7-23. doi: 10.1038/nrn3379. PMID: 23254191.