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Neurotrophin-3

Neurotrophin-3 (NT-3), also known as neurotrophic factor 3, is a secreted protein belonging to the neurotrophin family of growth factors that play crucial roles in the survival, development, and maintenance of neurons in both the peripheral and central nervous systems.^[1] Encoded by the NTF3 gene located on human chromosome 12p13.31, NT-3 consists of a mature polypeptide of 119 amino acids derived from a 257-amino-acid preproprotein, sharing approximately 58% sequence similarity with nerve growth factor (NGF).^[2] First identified in 1990 through cloning based on sequence homologies with NGF and brain-derived neurotrophic factor (BDNF), NT-3 exhibits distinct biological activities and mRNA expression patterns that differentiate it from its family members, confirming its role as a unique neurotrophic factor essential for neuronal differentiation and embryonic nervous system development.^[3] NT-3 primarily acts by binding to the TrkC receptor tyrosine kinase, activating signaling pathways such as the MAPK/ERK cascade to promote neuronal survival and axonal growth, particularly in proprioceptive and visceral sensory neurons.^[1] It is broadly expressed across human tissues, with the highest levels in the ovary and spleen, as well as in the adult brain and placenta, where it supports the maintenance of the mature nervous system and influences processes like nerve growth factor signaling and nervous system development.^[1] In animal models, such as NT-3-deficient mice, disruption of the gene leads to severe impairments, including loss of sensory and sympathetic neurons, movement defects in limbs, and cardiovascular abnormalities like septal defects, underscoring NT-3's critical involvement in both neural and cardiac ontogeny.^[2] Research has highlighted NT-3's potential in regenerative medicine, as it promotes peripheral nerve regeneration by sustaining a repair state in Schwann cells following chronic denervation through TrkC/ERK signaling, and it has been studied for its neuroprotective effects in conditions involving noradrenergic neuron degeneration.^[1] Additionally, NT-3 exhibits chemoattractant activity during fetal development and modulates signal transduction in various neuronal populations, positioning it as a key regulator in both developmental and adult neural homeostasis.^[1]

Discovery and Genetics

Discovery

Neurotrophin-3 (NT-3) was identified in 1990 as the third member of the neurotrophin family through independent molecular cloning efforts by two research groups, leveraging sequence similarities between nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). NGF had been discovered in the 1950s by Rita Levi-Montalcini and Stanley Cohen through bioassays on sympathetic and sensory neurons, earning them the 1986 Nobel Prize in Physiology or Medicine. BDNF was purified and characterized in 1982 by Yves-Alain Barde and colleagues from porcine brain extracts as a survival factor for embryonic chick dorsal root ganglion neurons. Building on these foundations, Maisonpierre et al. cloned the NT-3 gene from human and rat cDNA libraries using degenerate oligonucleotide probes based on conserved regions of NGF and BDNF, revealing a protein with approximately 58% identity to NGF and 50-55% to BDNF in the mature sequence.^[4] In parallel, Rosenthal et al. cloned a novel human neurotrophin gene, also designating it NT-3, and demonstrated its expression across a broad range of peripheral tissues and the central nervous system, distinct from NGF and BDNF distributions. The initial characterization involved expressing recombinant NT-3 in mammalian cells to assess biological activity. Early functional assays revealed that NT-3 potently supported the survival and neurite outgrowth of embryonic chick dorsal root ganglion neurons, particularly those from placode-derived nodose ganglia, while showing limited effects on sympathetic neurons responsive to NGF—thus distinguishing its target specificity within the family. These findings positioned NT-3 as a unique contributor to neuronal development.^[5]^[4] Throughout the 1990s, subsequent studies expanded on these discoveries by mapping NT-3 mRNA expression in embryonic and adult tissues, including high levels in the developing nervous system, heart, and kidney. For instance, in situ hybridization analyses confirmed widespread but patterned expression during embryogenesis, correlating with regions of sensory and motor neuron innervation. Gene targeting experiments in mice, such as those generating NT-3 null mutants, demonstrated severe deficits in proprioceptive and mechanoreceptive sensory neurons, underscoring NT-3's critical role as a target-derived growth factor for maintaining sensory and motor neuron populations. These milestones established NT-3's essential function in nervous system survival and plasticity.^[4]

Gene Characteristics

The NTF3 gene, which encodes neurotrophin-3 (NT-3), is located on the short arm of human chromosome 12 at position 12p13.31. It spans approximately 65 kilobases (kb) and consists of four exons, with the primary coding sequence contained within the terminal exon across its transcripts.^[1] The orthologous genes in rodents are situated on chromosome 6, reflecting conserved synteny in this genomic region.^[6]^[7] The full-length NTF3 coding sequence produces a 257-amino-acid prepro-NT-3 precursor protein. This precursor undergoes post-translational processing, including cleavage of a 27-amino-acid N-terminal signal peptide and a 111-amino-acid pro-domain, to yield the mature 119-amino-acid NT-3 polypeptide.^[4] The promoter region of NTF3 contains binding sites for transcription factors of the Sp family, such as Sp3 and Sp4, which positively regulate its transcription in neuronal contexts. Expression of NTF3 is modulated by neural activity during development, as well as upregulated in response to peripheral nerve injury, contributing to adaptive responses in the nervous system. The NTF3 gene exhibits high evolutionary conservation, with the mature NT-3 protein sharing approximately 95% sequence identity across mammalian species and 100% identity in human, mouse, and rat. Key structural features, including the six cysteine residues essential for intramolecular disulfide bonds and dimer formation, are invariantly preserved.^[8]^[4]

Structure and Biosynthesis

Protein Structure

Neurotrophin-3 (NT-3) exists as a mature homodimer with a molecular weight of approximately 27 kDa, consisting of two non-covalently associated monomers each comprising 119 amino acids and weighing about 13.6 kDa.^[8]^[9] Each monomer features a characteristic cystine-knot motif, where six conserved cysteine residues form three intramolecular disulfide bonds that stabilize the core structure.^[9] This motif is common to all neurotrophins and contributes to the protein's compact fold.^[10] The crystal structure of the NT-3 homodimer, determined at 2.4 Å resolution, reveals that each protomer adopts a twisted four-stranded β-sheet core, with the strands connected by loops that extend from the surface.^[9] These variable loop regions, particularly those in the N- and C-terminal domains, differ from those in other neurotrophins and are key to receptor specificity.^[9] A structure at 2.6 Å resolution of NT-3 in complex with p75^NTR further highlights the β-sheet-rich core and shows how the symmetrical dimer interface facilitates binding to the receptor ectodomain.^[11] NT-3 shares 50-60% amino acid sequence identity with nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-4 (NT-4), particularly in the conserved β-sheet regions and cystine-knot framework. However, its unique loop configurations, such as elongated loops in the central β-hairpin, confer selectivity for the TrkC receptor over TrkA or TrkB.^[9] The homodimer is highly stable, reflecting strong non-covalent interactions at the dimer interface involving hydrogen bonds and hydrophobic contacts.^[9] Additionally, NT-3 exhibits pH-sensitive conformational changes that may influence its stability and receptor interactions in endosomal environments.

Biosynthesis and Processing

Neurotrophin-3 (NT-3) is transcribed from the NTF3 gene, with mRNA expression prominently observed during embryonic development in various tissues. In rodents, NTF3 mRNA is detected in the central nervous system (CNS), particularly in the hippocampus and cortex, where levels are elevated around embryonic day 16 (E16) and peak during early postnatal stages before declining in adulthood.^[12] In the peripheral nervous system (PNS), expression occurs in dorsal root ganglia, supporting sensory neuron development, with transcripts present from early embryonic stages and peaking during target innervation phases around E13-E15.^[13] Non-neural tissues also show robust NTF3 expression, including the gut mesenchyme by E12.5, where it localizes to smooth muscle and lamina propria by E15.5, and skin, contributing to epithelial-mesenchymal interactions during embryogenesis.^[14]^[15] Overall, NTF3 mRNA levels across these sites peak during critical developmental windows, such as early target field innervation, before decreasing postnatally to support maturation.^[13] Following translation, pro-NT-3 undergoes post-translational processing primarily in the Golgi apparatus, where furin and other proprotein convertases cleave the precursor to yield the mature ~27 kDa NT-3 dimer.^[16] This endoproteolytic cleavage is essential for bioactivity, as the unprocessed proneurotrophin form (pro-NT-3) exhibits distinct functions, including induction of apoptosis in neurons via binding to the p75 neurotrophin receptor (p75NTR) in complex with sortilin.^[17]^[18] The processing efficiency varies by cell type, with most pro-NT-3 directed to the constitutive secretory pathway in hippocampal neurons, though coexpression with brain-derived neurotrophic factor (BDNF) can redirect it to regulated vesicles.^[16] Mature NT-3 is secreted in an activity-dependent manner from neurons and glial cells, facilitating local signaling in response to depolarization or synaptic activity.^[19] Upon release, NT-3 exhibits a short half-life in vivo, on the order of minutes, due to rapid diffusion through tissues and cerebrospinal fluid, as well as receptor-mediated endocytosis and degradation.^[20] This transient presence underscores its role in precise, localized trophic support during development and injury. In response to injury, such as hypoxia or ischemia, NT-3 expression is upregulated via hypoxia-inducible factor-1 (HIF-1), which binds to hypoxia response elements in the NTF3 promoter, enhancing transcription to promote neuroprotection and repair.^[21]^[22]

Receptors

High-Affinity Receptors

Neurotrophin-3 (NT-3) primarily exerts its effects through binding to its high-affinity receptor, TrkC, a transmembrane receptor tyrosine kinase encoded by the NTRK3 gene located on chromosome 15q25. TrkC is expressed prominently on sensory, motor, and sympathetic neurons during development and in adulthood, facilitating NT-3-mediated signaling essential for neuronal survival and differentiation. The binding affinity of NT-3 to TrkC is exceptionally high, with a dissociation constant (K_d) of approximately 1.8 × 10^-11 M, enabling potent and specific activation at physiological concentrations.^[23]^[24]^[23] The structure of TrkC supports its role as a selective NT-3 receptor. The extracellular domain features two cysteine-rich clusters (C1 and C2), three leucine-rich repeats (LRR1–3), and two immunoglobulin-like (Ig-like) domains (Ig1 and Ig2), which collectively mediate high-specificity binding to NT-3. The intracellular portion contains a tyrosine kinase domain with five key tyrosine residues that undergo autophosphorylation upon ligand binding, initiating downstream signaling. Alternative splicing of NTRK3 generates multiple isoforms, including full-length TrkC (e.g., TrkC.FL), which possesses an active kinase domain capable of robust signaling, and truncated forms (e.g., TrkC.T1), which lack the kinase domain and act as modulators, potentially by sequestering ligand or forming heterodimers with full-length receptors. Although NT-3 exhibits weak binding to other Trk receptors, such as TrkB (encoded by NTRK2; K_d ≈ 10^-9 M) and TrkA (encoded by NTRK1), these interactions are significantly less potent than with TrkC.^[25]^[25]^[26] TrkC expression is particularly elevated in proprioceptive neurons of the dorsal root ganglia and cerebellar granule cells, underscoring its specialized roles in sensory and cerebellar circuitry. Genetic studies have demonstrated that TrkC is indispensable for NT-3 responsiveness; targeted deletion of all trkC isoforms in mice results in phenotypes nearly identical to those observed in NT-3 knockout models, including profound loss of proprioceptive and certain sensory neurons, confirming TrkC as the critical mediator of NT-3's high-affinity signaling.^[24]

Low-Affinity Receptors

The low-affinity neurotrophin receptor, known as p75^NTR or NGFR, is encoded by the NGFR gene located on chromosome 17q21.33 and serves as a binding partner for all mature neurotrophins, including neurotrophin-3 (NT-3), with a dissociation constant (K_d) of approximately 1-10 nM (10^-9 M). As a member of the tumor necrosis factor receptor (TNF-R) superfamily, p75^NTR is ubiquitously expressed in neural tissues, where it modulates neurotrophin signaling in both neurons and glial cells.^[27] Structurally, p75^NTR is a type I transmembrane glycoprotein featuring an extracellular domain with four cysteine-rich domains (CRD1-CRD4) responsible for ligand binding and an intracellular region containing a juxtamembrane "chopper" domain and a death domain that facilitates interactions with signaling adaptors.^[27] The cysteine-rich domains enable the formation of dimeric complexes with neurotrophins, while the death domain links to pro-apoptotic pathways upon activation by proneurotrophins.^[28] In the context of NT-3 signaling, p75^NTR interacts with the high-affinity receptor TrkC to enhance its binding affinity and specificity for NT-3, thereby promoting neuronal survival and differentiation in responsive cells. Additionally, p75^NTR binds pro-NT-3 with higher affinity than mature NT-3, triggering apoptosis in non-surviving neurons through activation of the c-Jun N-terminal kinase (JNK) pathway.^[27] p75^NTR is co-expressed with Trk receptors, including TrkC, in developing neurons during critical periods of neural circuit formation, supporting processes like axonal outgrowth and synapse refinement.^[27] In adulthood, its expression levels generally decrease but can be upregulated following neural injury, contributing to regenerative or degenerative responses in affected tissues.

Mechanism of Action

Receptor Binding and Activation

Neurotrophin-3 (NT-3), existing as a homodimer, initially binds to the extracellular domain of the high-affinity receptor TrkC, primarily through its second immunoglobulin-like (Ig2) domain, thereby inducing dimerization of TrkC monomers or stabilizing preformed dimers.^[29] This ligand-induced dimerization repositions the intracellular kinase domains of TrkC, enabling trans-autophosphorylation. In the presence of the low-affinity receptor p75^NTR, NT-3 recruits p75^NTR to form a ternary complex with TrkC, which enhances binding affinity through accelerated association kinetics and reduced dissociation rates.^[30]^[31] The kinetics of NT-3 binding to TrkC facilitate rapid complex formation, followed by a conformational change that exposes the TrkC kinase domain for autophosphorylation on key tyrosine residues such as Y516 and Y816. This activation step is essential for initiating downstream signaling while maintaining specificity to TrkC over other Trk receptors. Specificity of NT-3 for TrkC is governed by interactions between NT-3's variable loop 4 and the Ig2 domain of TrkC. In contrast, NT-3's weaker binding to TrkB relies on conserved residues in the central β-strand bundle, resulting in lower affinity and reduced activation efficiency compared to its primary interaction with TrkC. Experimental evidence from crystal structures of the NT-3/TrkC complex reveals the role of non-covalent interactions in stabilizing the active conformation.^[32]

Downstream Signaling Pathways

Upon ligand binding, neurotrophin-3 (NT-3) induces dimerization and autophosphorylation of the TrkC receptor tyrosine kinase, primarily at tyrosine residues Y490, Y785, and others in the intracellular domain, which serve as docking sites for downstream signaling adapters.^[33] This autophosphorylation recruits Shc or fibroblast growth factor receptor substrate 2 (Frs2) to Y490, activating the Ras-MAPK/ERK cascade that promotes neuronal proliferation and differentiation through sustained ERK activation.^[34] Concurrently, the PI3K/Akt pathway is initiated via direct or indirect recruitment to TrkC, leading to Akt phosphorylation and inhibition of pro-apoptotic factors like BAD, thereby enhancing neuronal survival.^[33] Additionally, phospholipase Cγ (PLCγ) docks at phospho-Y785, cleaving phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), which trigger intracellular calcium release and protein kinase C (PKC) activation to support neurotransmitter secretion and synaptic strengthening.^[33] These pathways exhibit rapid kinetics, with TrkC autophosphorylation occurring post-NT-3 binding in neuronal cultures.^[35] NT-3 can also engage the low-affinity p75NTR receptor, often in conjunction with the co-receptor sortilin, to modulate survival versus death decisions in a context-dependent manner.^[36] Pro-NT-3 binding to the p75NTR-sortilin complex activates the JNK pathway and downstream caspases, promoting apoptosis in competing or excess neurons during development by upregulating pro-apoptotic proteins like Bax.^[37] In contrast, mature NT-3 signaling through p75NTR can stimulate NF-κB activation via TRAF6 and IKK, fostering anti-apoptotic gene expression and cell survival in select neuronal populations.^[33] The kinase inhibitor K252a effectively blocks TrkC autophosphorylation, thereby abolishing these downstream cascades and NT-3-mediated effects in experimental models.^[34] NT-3/TrkC signaling exhibits cross-talk with BDNF/TrkB pathways, particularly in the hippocampus, where integrated activation influences synaptic function.^[38] The duration of ERK activation plays a critical role: sustained ERK signaling correlates with survival and structural synapse remodeling, while transient activation supports plasticity and functional modifications without long-term commitment.^[39] This temporal distinction allows NT-3 to fine-tune neuronal responses in concert with BDNF, optimizing network adaptability.^[38]

Biological Functions

Roles in Neural Development

Neurotrophin-3 (NT-3) plays a critical role in the proliferation and differentiation of neural crest-derived precursors during early neural development. It acts as a mitogen for cultured neural crest cells, increasing thymidine incorporation by up to 8.4-fold and cell numbers by 2- to 4.8-fold in mixed neural crest/somite cultures, thereby promoting the expansion of sensory neuron precursors.^[40] This proliferative effect is enhanced in the presence of somite cells and laminin substrates, highlighting NT-3's influence on the initial phases of neural crest cell growth. Furthermore, NT-3 is essential for the survival of specific neural crest-derived populations, including sympathetic neurons, where its absence leads to a significant reduction in sympathetic ganglion size, and enteric neurons, where it induces differentiation of crest-derived cells into neurons or glia in fetal gut cultures.^[41]^[42] In axon guidance and targeting, NT-3 functions as a chemoattractant for proprioceptive sensory afferents, directing their pathfinding to appropriate spinal cord targets via its high-affinity receptor TrkC. In vivo studies using NT-3/Bax double-knockout mice demonstrate that proprioceptive axons reach the dorsal spinal cord but fail to properly innervate ventral horn motor neurons, resulting in ectopic branching or midline crossing.^[43] In vitro, NT-3 gradients from soaked beads attract dorsal root ganglion axons over distances up to 1,200 μm, confirming its role in short-range guidance for establishing monosynaptic connections in the stretch reflex arc. Additionally, NT-3 contributes to sensory axon branching in limb targets, interacting with factors such as GDNF to support motor pool specification and circuit assembly.^[44] Studies of NT-3 null mice reveal profound developmental deficits, underscoring its necessity in neural organization. These mice exhibit substantial loss of sensory neurons in dorsal root ganglia, particularly proprioceptive and mechanoreceptive subtypes, along with severe ataxia characterized by abnormal limb clasping and uncoordinated movements.^[41] By birth, they also show a complete absence of muscle spindles in hindlimbs, reflecting impaired sensory innervation. NT-3 expression peaks during embryonic days 12 to postnatal day 0 (E12-P0) in rodents, coinciding with critical periods of neural crest migration, precursor proliferation, and axon targeting.^[41]

Functions in the Adult Nervous System

In the adult nervous system, neurotrophin-3 (NT-3) plays a key role in synaptic plasticity, particularly by enhancing long-term potentiation (LTP) in the hippocampus through activation of its high-affinity receptor TrkC. This enhancement occurs via the CaMKIV–CREB pathway in presynaptic neurons, leading to sustained increases in synaptic efficacy, such as a ~2.5-fold rise in spontaneous synaptic current frequency over 48 hours.^[45] Additionally, NT-3 supports structural modifications like dendritic spine remodeling in the cortex via the Rap1–MAPK pathway, promoting synapse growth independent of CREB activation and potentially aiding in learning and memory processes.^[45] Endogenous NT-3 also regulates short-term plasticity at hippocampal perforant path–granule cell synapses, where its reduction in heterozygous mice decreases paired-pulse facilitation by approximately 25% at short interstimulus intervals, underscoring its maintenance of synaptic transmission efficiency in mature circuits.^[46] NT-3 contributes to adult neurogenesis and repair mechanisms, notably by promoting neuronal differentiation in the hippocampal dentate gyrus without affecting progenitor proliferation. In conditional NT-3 knockout mice, the number of BrdU+/NeuN+ mature neurons decreases significantly (P < 0.01), correlating with impaired LTP at lateral perforant path synapses (121% vs. 156% in wild-type) and deficits in spatial memory.^[47] Post-injury, NT-3 expression is upregulated in the peripheral nervous system (PNS) to sustain Schwann cell repair phenotypes via the TrkC/ERK/c-Jun pathway, peaking c-Jun levels at 5 weeks after denervation and enhancing axon regeneration, myelination, and neuromuscular reinnervation in adult models.^[48] For sensory maintenance, NT-3 sustains the function of specific mechanoreceptors and nociceptors in the adult periphery. It is essential for preserving cutaneous slowly adapting (SA) mechanoreceptors and D-hair afferents, with NT-3 heterozygous adult mice showing an 80% loss of SA afferents due to Merkel cell depletion, critical for fine tactile discrimination.^[49] In nociceptors, NT-3 attenuates thermal hyperalgesia by reducing TRPV1 receptor expression in dorsal root ganglion neurons (from ~56% to ~26% of small-to-medium cells) following chronic constriction injury, via suppression of p38 MAPK activation, though it spares mechanical sensitivity.^[50] NT-3 infusion further restores proprioception in aging models; delayed peripheral administration in elderly rats (starting 24 hours post-corticospinal injury) normalizes proprioceptive reflexes and improves sensorimotor recovery on ladder-walking tasks through corticospinal sprouting.^[51] Beyond neural roles, NT-3 influences non-neural functions, including regulation of gut motility through enteric neurons and peripheral immune cell modulation. In adult rats, intravenous NT-3 inhibits gastric motility (partially vagally mediated) while attenuating postoperative colonic ileus, without altering baseline colonic propulsion, highlighting its role in enteric nervous system homeostasis.^[52] Recent research demonstrates NT-3's impact on peripheral immune cell survival and activation; ex vivo treatment reduces T cell (CD4+ and CD8+) and monocyte activation in human peripheral blood mononuclear cells post-stroke, decreasing pro-inflammatory cytokines like IFN-γ and TNF-α via TrkC signaling, with effects varying by cell type and age.^[53]

Clinical Significance

Role in Diseases

Primary associations with congenital insensitivity to pain with anhidrosis (CIPA) involve mutations in NTRK1 rather than NTF3. However, dysregulation of the NT-3/TrkC signaling pathway plays a role in oncogenesis; for instance, variants and altered expression of TrkC (NTRK3) are observed in medulloblastoma, where high TrkC levels correlate with a favorable prognosis due to induction of apoptosis in tumor cells.^[54]^[55] In neurodegenerative diseases, altered NT-3 expression contributes to pathology. In amyotrophic lateral sclerosis (ALS) models, NT-3 supplementation mitigates motor neuron loss and improves neuromuscular function.^[56] Similarly, in Alzheimer's disease (AD), NT-3 has been implicated in maintaining hippocampal integrity, with studies exploring its therapeutic role in reducing cognitive decline.^[57] NT-3 deficiency is implicated in peripheral neuropathies, where it leads to sensory deficits and delayed repair. In diabetic neuropathy, loss of NT-3 signaling promotes mitochondrial dysfunction in sensory neurons, contributing to axonal degeneration and sensory loss, although compensatory increases in NT-3 have been noted in some human skin samples.^[58] Following peripheral nerve injury, downregulation of NT-3 hinders Schwann cell repair phenotypes and axon regeneration in the peripheral nervous system (PNS), as NT-3 normally sustains c-Jun expression to facilitate remyelination and outgrowth.^[59] Beyond neurological disorders, NT-3 dysregulation influences metabolic and pain-related conditions. In obesity, adipose tissue-derived NT-3 regulates sympathetic innervation and energy expenditure via the TrkC pathway, with altered expression linked to adipocyte hypertrophy and metabolic imbalance, though direct gut-specific roles remain under investigation.^[60] NT-3 is implicated in chronic pain syndromes, where it modulates sodium channel expression and hyperalgesia; for example, in chemotherapy-induced neuropathic pain, NT-3 exacerbates mechanical hypersensitivity through TrkC activation.^[61] Recent 2024 research demonstrates NT-3's involvement in multiple sclerosis (MS) demyelination, as NT-3 gene therapy in experimental autoimmune encephalomyelitis models reduces immune-mediated myelin loss and promotes remyelination.^[62]

Therapeutic Potential

Gene therapy approaches utilizing adeno-associated virus (AAV) vectors to deliver neurotrophin-3 (NT-3) have demonstrated significant potential in preclinical models of spinal cord injury (SCI). In rodent models during the 2010s, intramuscular or intrathecal administration of AAV-NT3 vectors promoted axonal regeneration and restored locomotor function, such as skilled stepping and coordinated swimming, by enhancing propriospinal and descending motor pathways after contusive injury.^[63]^[64] Preclinical evidence supports NT-3's neurotrophic effects for motor neuron survival in amyotrophic lateral sclerosis (ALS), with ongoing research into remyelination and neuroprotection.^[65] Recombinant NT-3 has been evaluated in early clinical trials since the 1990s for motor neuropathies, including diabetic polyneuropathy and Charcot-Marie-Tooth disease type 1A (CMT1A). Subcutaneous injections in small cohorts showed improvements in sensory nerve function and increases in myelinated fiber density on nerve biopsies, indicating enhanced axonal regeneration and Schwann cell support. A phase I/IIa trial of AAV1.NT-3 for CMT1A (NCT03520751) was suspended in 2022 due to vector manufacturing complications.^[66]^[67] However, these trials reported side effects such as injection-site pain, mild paresthesia, and gastrointestinal issues like diarrhea, which limited tolerability at higher doses.^[68] To address stability and half-life challenges, modern formulations incorporate PEGylation, where polyethylene glycol conjugation to NT-3 nanoparticles improves serum resistance, controlled release, and bioavailability for sustained therapeutic delivery in neuropathy models.^[69] Small-molecule TrkC agonists, designed to mimic NT-3 signaling, offer an oral alternative for neurodegeneration treatment. Compounds like LM22B-10 act as partial agonists at TrkB/TrkC receptors, promoting neuronal survival and synaptic plasticity in preclinical models of Alzheimer's and other degenerative conditions without the immunogenicity risks of protein therapeutics.^[70] Recent research from 2023–2024 has explored NT-3's role in enhancing stem cell differentiation for Parkinson's disease, where NT-3 supplementation promotes dopaminergic neuron maturation from neural progenitors in animal models of MPTP-induced parkinsonism, potentially aiding cell replacement therapies.^[71] Key challenges in NT-3 therapeutics include poor blood-brain barrier (BBB) penetration, which limits central nervous system access; intranasal delivery routes have emerged as a noninvasive solution, enabling direct nose-to-brain transport of NT-3 and other neurotrophins while bypassing the BBB for rapid CNS distribution.^[72] Advances in combination therapies pair NT-3 with brain-derived neurotrophic factor (BDNF) to achieve synergistic effects in neuropathy, as preclinical studies show enhanced axonal outgrowth and functional recovery beyond single-agent treatment, informing ongoing trial designs for peripheral nerve disorders.^[73]

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The Neurotrophin Receptor p75 Binds Neurotrophin-3 on ...
Jul 15, 1997 · Thus, both p75NTR and full-length trkC are involved in NT3 high-affinity binding on freshly dissociated neurons. Similar results were obtained ...Missing: enhances | Show results with:enhances
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The Conundrum of the High-Affinity NGF Binding Site Formation ...
A ternary TrkA/NGF/p75 NTR complex is assumed to be crucial for the formation of the so-called high-affinity NGF binding sites.
[32]
High affinity nerve growth factor binding displays a faster rate of ...
When both p140trk and p75NGFR receptors are coexpressed, the rate of association of NGF is increased 25-fold to produce a higher affinity binding site.
[33]
1WWC: NT3 BINDING DOMAIN OF HUMAN TRKC RECEPTOR
The crystal structures of the ligand binding domain of TrkA, TrkB, and TrkC were solved and refined to high resolution. The domains adopt an immunoglobulin-like ...
[34]
Neurotrophin-regulated signalling pathways - PMC - PubMed Central
This depicts the interactions of each neurotrophin with Trk and p75NTR receptors and major intracellular signalling pathways activated through each receptor.
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https://rupress.org/jcb/article/138/2/411/655/Rapid-Retrograde-Tyrosine-Phosphorylation-of-trkA
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Rapid Retrograde Tyrosine Phosphorylation of trkA and Other ...
... phosphorylation within 5–15 min. However, no detectable 125I-NGF appeared in the cell bodies/proximal axons within 30–60 min of its addition to distal axons.
[37]
Neurotrophins and their involvement in digestive cancers - Nature
Feb 11, 2019 · Fig. 2: mNT/Trk pro-survival signaling involving the RAS-MAPK, PI3K/AKT, PLC gamma (γ) downstream pathways.
[38]
Three-tier regulation of cell number plasticity by neurotrophins and ...
In this study, we show that DNTs and Tolls can switch from promoting cell survival to death in the central nervous system (CNS) via a three-tier mechanism.
[39]
Neurotrophin 3 induces structural and functional modification of ...
Dec 18, 2006 · Cross talk between ERK and PKA is required for Ca2+ stimulation of CREB-dependent transcription and ERK nuclear translocation. Neuron. 21.Requirement Of Rap1, But Not... · Camkiv--Creb Pathway... · Rap1--Mapk Pathway Mediates...
[40]
Neurotrophin receptors: mediators of life and death - ScienceDirect
A sustained vs. transient duration in signaling may determine which pathway is dominant. Interestingly, other neurotrophins such as BDNF and NT-3, which ...
[41]
Neurotrophin 3 is a mitogen for cultured neural crest cells. - PNAS
ABSTRACT. Neurotrophin 3 (NT-3) promotes the survival and induces neurite outgrowth from a subset of neural crest. (NC) and placode-derived neurons.
[42]
Severe sensory and sympathetic deficits in mice lacking ... - Nature
Jun 23, 1994 · Differential Effects of AAV.BDNF and AAV.Ntf3 in the Deafened Adult Guinea Pig Ear. Cameron L. Budenz; Hiu Tung Wong; Yehoash Raphael.
[43]
Neurotrophin-3 induces neural crest-derived cells from fetal rat gut ...
Nov 1, 1994 · It is concluded that NT-3 specifically promotes the differentiation of enteric crest ... role in the development and/or maintenance of the ENS.
[44]
A Chemoattractant Role for NT-3 in Proprioceptive Axon Guidance
Our results show that survival factor NT-3 acts as a short-distance axon guidance molecule for muscle sensory afferents as they approach their proper targets.
[45]
Peripheral NT3 Signaling Is Required for ETS Protein Expression ...
NT3 expression by motor neurons does not appear to be required for the induction of ER81 in DRG. Moreover, peripheral NT3 can restore both the expression of ...Missing: rodent | Show results with:rodent
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https://doi.org/10.1523/JNEUROSCI.18-21-08730.1998
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https://doi.org/10.1101/lm.76006
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https://doi.org/10.1186/s12967-023-04609-2
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https://doi.org/10.1016/S0896-6273(00)80047-1
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https://doi.org/10.1523/JNEUROSCI.3909-04.2005
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https://doi.org/10.4103/1673-5374.257518
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https://pubmed.ncbi.nlm.nih.gov/17973633/
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https://doi.org/10.1016/j.expneurol.2021.113901
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Activation of Neurotrophin-3 Receptor TrkC Induces Apoptosis in ...
The decreased growth and proliferation rates in NT-3-stimulated Daoy-trkC cultures indicate that NT-3 induces apoptosis without increasing proliferation. These ...
[55]
Activation of neurotrophin-3 receptor TrkC induces apoptosis in ...
Elevated expression of the neurotrophin-3 (NT-3) receptor TrkC by childhood medulloblastomas is associated with favorable clinical outcome.Missing: variants | Show results with:variants
[56]
Analysis of Neurotrophic Factors in Limb and Extraocular Muscles of ...
... neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4) and glial cell line-derived neurotrophic factor (GDNF) in limb muscles and extraocular muscles (EOMs) from ...
[57]
Recombinant neurotrophin-3 with the ability to penetrate the blood ...
In AD patients, reduced levels of NT-3 are closely associated with hippocampal neuronal loss, decreased synaptic density, and cognitive decline [15].
[58]
Neurotrophin-3 prevents mitochondrial dysfunction in sensory ...
Therefore, we hypothesized that loss of NT-3 may contribute to mitochondrial dysfunction in sensory neurons in diabetic sensory neuropathy. The specific aim ...
[59]
Neurotrophin-3 promotes peripheral nerve regeneration by ...
NT-3 promoted peripheral nerve regeneration after chronic denervation, mainly by upregulating or maintaining a high level of c-Jun rather than NT-3 itself. The ...
[60]
Adipose tissue-derived neurotrophic factor 3 regulates sympathetic ...
NT-3 is a fat-derived neurotrophic factor that regulates SNS innervation, energy metabolism and obesity.Missing: gut | Show results with:gut
[61]
NT-3 contributes to chemotherapy-induced neuropathic pain ...
Apr 9, 2024 · Cancer patients undergoing treatment with antineoplastic drugs often experience chemotherapy-induced neuropathic pain (CINP), ...
[62]
AAV1.NT3 gene therapy mitigates the severity of autoimmune ...
Feb 19, 2025 · NT-3 gene therapy is well positioned for suppressing immune reactions against CNS myelin, providing remyelination and axon protection to reverse ...
[63]
Descending motor circuitry required for NT-3 mediated locomotor ...
Dec 20, 2019 · Here we functionally dissected the role of descending neural pathways in response to NT-3-mediated recovery after a T9 contusive SCI in mice.Missing: specification | Show results with:specification
[64]
Delayed viral vector mediated delivery of neurotrophin-3 improves ...
We have shown that delayed intramuscular AAV-NT3 treatment can promote recovery in skilled stepping and coordinated swimming.
[65]
Gene specific therapies – the next therapeutic milestone in neurology
Sep 8, 2020 · A clinical trial has not yet been announced. Further, the upregulation of neurotrophin-3 (NT-3) has been shown to lead to a remyelination in ...Motor Neuron Disorders · Movement Disorders · Muscle Diseases
[66]
Challenges in Treating Charcot-Marie-Tooth Disease and Related ...
The NT-3 story started with a pilot study on eight CMT1A patients treated with injections of recombinant NT-3: nerve biopsies revealed an increase in myelinated ...
[67]
Tolerability of recombinant-methionyl human neurotrophin-3 (r ...
The most frequently recorded adverse effects were mild injection-site pain, diarrhea, and elevation of liver function tests. No change in neurologic ...
[68]
The Impact of Serum Protein Adsorption on PEGylated NT3–BDNF ...
First, we focused on determining PEGylated NT3–BDNF NPs' stability in cell-free systems and then in retinal (ARPE-19) cells. The influence of serum exposure on ...
[69]
A small molecule TrkB/TrkC neurotrophin receptor co-activator with ...
A TrkB/TrkC-activating compound, LM22B-10, has been identified and characterized. LM22B-10 promotes greater survival of neurons than native neurotrophins.Missing: TP- 023
[70]
Neuroprotective effects of Neurotrophin-3 in MPTP-induced ...
Another reason could be due to the short half-life of NT3 itself following in vivo injection and its ability to sustain the trophic effects after injection ...
[71]
Intranasal delivery of neurotrophic factors BDNF, CNTF, EPO, and ...
The intranasal delivery method has great clinical potential due to (1) simplicity of administration, (2) noninvasive drug administration, (3) relatively rapid ...
[72]
Combined brain-derived neurotrophic factor and neurotrophin-3 ...
Sep 25, 2022 · In this study, we aimed to investigate whether treatment with both BDNF and NT-3 (Cocktail) is superior to treatment with each neurotrophin separately.Missing: Maisonpierre purification uterus 1990