Disease relevance of Ntrk2

• Thus, TrkB agonists and antagonists deserve exploration as novel hair growth-modulatory drugs for the management of common hair growth disorders [1].
• In the vestibular system TrkB or TrkC activation is sufficient to promote vestibular ganglion neuron survival, while TrkB activation is required to promote proper innervation and synaptogenesis [2].
• However, repeated intrathecal injection of a specific antibody to truncated TrkB, which lacks the cytoplasmic protein tyrosine kinase domain, failed to reverse thermal hyperalgesia observed in nerve-ligated mice [3].
• Coronary vessel development requires activation of the TrkB neurotrophin receptor by the Wilms' tumor transcription factor Wt1 [4].
• In vivo, dominant-negative manipulation of TrkB signaling using adenovirus to overexpress trkB.t1 in mouse sternomastoid muscle fibers resulted in the disassembly of postsynaptic AChR clusters at neuromuscular junctions, similar to that observed in mutant trkB+/- mice [5].
• A single intrahypothalamic application of minute amounts of NT4 or an agonist trkB antibody also reduced food intake and body weight in mice [6].

Psychiatry related information on Ntrk2

• We asked whether this exuberance is attributable to abnormal TrkB signaling, because modulation of TrkB signaling during a critical period dramatically influences the segregation and the morphology of TCAs in layer IV of the visual cortex [7].

High impact information on Ntrk2

• In contrast with mice lacking the BDNF receptor TrkB, motor neurons appear normal in the BDNF mutant [8].
• We have generated mice carrying a germline mutation in the tyrosine kinase catalytic domain of the trkB gene [9].
• We previously identified two tyrosine protein kinase genes, designated trk and trkB, that code for putative neurogenic cell surface receptors [10].
• However, only gp145trkB contains a long cytoplasmic region, which includes a catalytic tyrosine protein kinase domain. trkB transcripts coding for this protein were observed in the cerebral cortex and the pyramidal cell layer of the hippocampus [10].
• These results suggest that another ligand, perhaps NT3, does indeed act on TrkB in vivo [11].

Chemical compound and disease context of Ntrk2

• Unliganded c-erbA/thyroid hormone receptor induces trkB expression in neuroblastoma cells [12].
• The objective of the present study was to examine this; changes in contents of brain-derived neurotrophic factor and TrkB protein were monitored by immunohistochemistry during kainic acid-induced hypertrophy [13].

Biological context of Ntrk2

• Mice lacking TrkB show a more severe phenotype than mice lacking BDNF, suggesting that TrkB may act as a receptor for additional ligands in vivo [11].
• However, in double mutant mice, we now show that reducing the expression of both TrkB and TrkC causes massive cell death of postnatal hippocampal and cerebellar granule neurons [14].
• Experiments in cell culture have revealed that an intact Shc adaptor binding site on TrkB and subsequent activation of the Ras/MAPK pathway are important for neuronal survival and neurite outgrowth [15].
• Ts16 neurons have normal levels of the TrkB tyrosine kinase receptor but an upregulation of the TrkB.T1 truncated receptor isoform [16].
• Point mutation in trkB causes loss of NT4-dependent neurons without major effects on diverse BDNF responses [15].

Anatomical context of Ntrk2

• Finally, mice with a disrupted Ntrk2 gene lacked a significant proportion of their intramyocardial blood vessels [4].
• Furthermore, the BDNF dose dependency displayed by these TrkB-expressing fibroblasts is similar to that required to support the survival of primary neurons [17].
• Correlating with the loss of granule cells, the number of mossy fibers projecting to CA3 pyramidal neurons was markedly reduced in mice carrying mutant trkB/trkC alleles, demonstrating impairment of excitatory pathways in the hippocampus [14].
• Distinct requirements for TrkB and TrkC signaling in target innervation by sensory neurons [18].
• Kinetic analysis of neuronal death in the hippocampus showed that dentate gyrus granule neurons become dependent on TrkB and TrkC after the first postnatal week, shortly after the period of naturally occurring cell death, indicating a role of these receptors in supporting postmitotic neurons [14].

Associations of Ntrk2 with chemical compounds

• Postsynaptic glutamate receptors are not affected by TrkB reduction, indicating that BDNF does not modulate plasticity through postsynaptic TrkB [19].
• First, each of the high-affinity tyrosine kinase receptors, trkA, trkB, and trkC, as well as the low-affinity p75 receptor has an impact on at least one type of mechanoreceptor [20].
• TrkB receptors mediate the effects of BDNF on striatal medium spiny neurons and mesencephalic dopamine neurons [21].
• Interactions between TrkB signaling and serotonin excess in the developing murine somatosensory cortex: a role in tangential and radial organization of thalamocortical axons [7].
• TrkB variants with deletions in the leucine-rich motifs of the extracellular domain [22].
• Brain monoamines seem to be critical mediators of antidepressant-induced TrkB activation, as antidepressants reboxetine and citalopram do not produce TrkB activation in the brains of serotonin- or norepinephrine-depleted mice [23].

Physical interactions of Ntrk2

• Surprisingly, most sets of trkA-dependent sensory innervation are suppressed by trkB perhaps interacting with p75 [24].
• A series of mutants with deletion in the extracellular portion of TrkB were expressed transiently and stably in mammalian cells to examine the brain-derived neurotrophic factor (BDNF)-binding properties of TrkB [25].

Co-localisations of Ntrk2

• Double immunofluorescence staining studies showed that TrkB was colocalized with cadherin and catenin at cell-cell contact sites [26].

Regulatory relationships of Ntrk2

• Haploinsufficiency for trkB and trkC receptors induces cell loss and accumulation of alpha-synuclein in the substantia nigra [27].
• Activation of Wt1 in an inducible cell line significantly enhanced TrkB expression [4].
• We find that increases in cAMP can rapidly activate the BDNF receptor TrkB and induce BDNF-dependent long-lasting potentiation at the Schaffer collateral-CA1 synapse in hippocampus [28].
• Exposure of mature cortical cultures for 48 h to NT-4/5 induced neuronal death through TrkB activation [29].
• TrkB-expressing cells were located above the NeuroD-positive layer in the middle compartment [30].

Other interactions of Ntrk2

• In the present paper, we use antibodies to TrkA, TrkB, and TrkC to characterize their expression patterns and to determine which subpopulations of cells are lost in mice lacking individual neurotrophins or Trk receptors [31].
• Characterization of neurotrophin and Trk receptor functions in developing sensory ganglia: direct NT-3 activation of TrkB neurons in vivo [31].
• In the inner ear, TrkB- and TrkC-dependent neurons were shown to at least partially depend on each other for survival, most likely indirectly due to abnormal development of their common targets [32].
• Our results suggest that signaling via TrkA, but not TrkB, may be involved in the postnatal regulation of AChE activity in the adrenal medulla and its preganglionic nerves [33].
• We conclude that impairment in trkB and/or trkC signaling induces a phenotype in the aged SN, which includes two hallmarks of PD, losses of TH positive neurons and axons along with massive neuronal deposits of alpha-synuclein [27].

Analytical, diagnostic and therapeutic context of Ntrk2

• Moreover, TrkB immunohistochemistry performed on sections of the developing wildtype and weaver cerebella revealed that only differentiated granule cells, but not the precursor cells, make high levels of TrkB receptor [34].
• TrkA, TrkB, TrkC, and gp75 were detected by immunofluorescence microscopy in 60-80% of cells [35].
• Expression of BDNF and TrkB in mouse taste buds after denervation and in circumvallate papillae during development [36].
• The expression of trkB transcripts was established by PCR analysis and in situ hybridization [37].
• In this study, the authors investigated whether reducing endogenous expression of TrkB-binding neurotrophins modifies the susceptibility to ischemic injury after 1-hour middle cerebral artery occlusion followed by 23 hours of reperfusion in a filament middle cerebral artery occlusion model [38].

References